chr12-27655169-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000318304.12(PPFIBP1):c.723G>A(p.Met241Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,535,582 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M241L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

PPFIBP1
ENST00000318304.12 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.89

Publications

0 publications found

Variant links:

Genes affected

PPFIBP1 (HGNC:9249): (PPFIA binding protein 1) The protein encoded by this gene is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. Liprins interact with members of LAR family of transmembrane protein tyrosine phosphatases, which are known to be important for axon guidance and mammary gland development. It has been proposed that liprins are multivalent proteins that form complex structures and act as scaffolds for the recruitment and anchoring of LAR family of tyrosine phosphatases. This protein was found to interact with S100A4, a calcium-binding protein related to tumor invasiveness and metastasis. In vitro experiment demonstrated that the interaction inhibited the phosphorylation of this protein by protein kinase C and protein kinase CK2. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

PPFIBP1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: STRONG Submitted by: G2P
neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities
Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

PPFIBP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035979718).

BP6

Variant 12-27655169-G-A is Benign according to our data. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-27655169-G-A is described in CliVar as Likely_benign. Clinvar id is 2344024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000886 (135/152292) while in subpopulation NFE AF = 0.00153 (104/68024). AF 95% confidence interval is 0.00129. There are 0 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPFIBP1	NM_003622.4 link	c.696+355G>A		intron_variant	Intron 8 of 29	ENST00000228425.11	NP_003613.4	Q86W92-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPFIBP1	ENST00000228425.11 link	c.696+355G>A		intron_variant	Intron 8 of 29	1	NM_003622.4	ENSP00000228425.6		Q86W92-2

Frequencies

GnomAD3 genomes

AF:

0.000887

AC:

135

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00153

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000807

AC:

112

AN:

138860

AF XY:

0.000854

show subpopulations

Gnomad AFR exome

AF:

0.000437

Gnomad AMR exome

AF:

0.000733

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00128

AC:

1769

AN:

1383290

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

846

AN XY:

682616

show subpopulations

African (AFR)

AF:

0.000348

AC:

AN:

31570

American (AMR)

AF:

0.000897

AC:

AN:

35692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25166

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35724

South Asian (SAS)

AF:

0.000480

AC:

AN:

79200

European-Finnish (FIN)

AF:

0.000117

AC:

AN:

34134

Middle Eastern (MID)

AF:

0.000527

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00150

AC:

1613

AN:

1078112

Other (OTH)

AF:

0.00116

AC:

AN:

58002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

163

245

326

408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000886

AC:

135

AN:

152292

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41556

American (AMR)

AF:

0.000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00153

AC:

104

AN:

68024

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000940

Hom.:

Bravo

AF:

0.000858

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00156

AC:

ExAC

AF:

0.000554

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Aug 30, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PPFIBP1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

T;.;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.036

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;.;L

PhyloP100

7.9

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.18

N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.013

D;D;D

Sift4G

Benign

0.19

T;T;T

Polyphen

0.79, 0.52

.;P;P

Vest4

0.40, 0.39

MutPred

0.18

.;.;Gain of methylation at K242 (P = 0.0737);

MVP

0.25

MPC

0.41

ClinPred

0.053

GERP RS

4.9

Varity_R

0.55

gMVP

0.21

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over