Genetic Variant PABIR3:p.Ser217Ala (chrX-134852859-T-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001388447.1(PABIR3):c.649T>G(p.Ser217Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,138,526 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000028 ( 0 hom. 7 hem. )

Consequence

PABIR3
NM_001388447.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.705

Publications

1 publications found

Variant links:

Genes affected

PABIR3 (HGNC:25202): (PABIR family member 3) Predicted to enable protein serine/threonine phosphatase inhibitor activity. Predicted to be involved in negative regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

PABIR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.073465794).

BS2

High Hemizygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR3	NM_001388447.1 link	c.649T>G	p.Ser217Ala	missense_variant	Exon 10 of 11	ENST00000645433.2	NP_001375376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR3	ENST00000645433.2 link	c.649T>G	p.Ser217Ala	missense_variant	Exon 10 of 11		NM_001388447.1	ENSP00000496338.1		A0A2R8Y7S4

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111875

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.000665

GnomAD2 exomes

AF:

0.0000114

AC:

AN:

87600

AF XY:

0.0000414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000282

AC:

AN:

1026651

Hom.:

Cov.:

AF XY:

0.0000213

AC XY:

AN XY:

328641

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24265

American (AMR)

AF:

0.0000401

AC:

AN:

24953

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18269

East Asian (EAS)

AF:

0.00

AC:

AN:

26315

South Asian (SAS)

AF:

0.00

AC:

AN:

46025

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4040

European-Non Finnish (NFE)

AF:

0.0000320

AC:

AN:

812468

Other (OTH)

AF:

0.0000457

AC:

AN:

43742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111875

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34013

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30797

American (AMR)

AF:

0.00

AC:

AN:

10447

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3602

South Asian (SAS)

AF:

0.00

AC:

AN:

2725

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5969

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53260

Other (OTH)

AF:

0.000665

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.405T>G (p.F135L) alteration is located in exon 6 (coding exon 6) of the FAM122C gene. This alteration results from a T to G substitution at nucleotide position 405, causing the phenylalanine (F) at amino acid position 135 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.3

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.017

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.28

M_CAP

Benign

0.0026

MetaRNN

Benign

0.073

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

PhyloP100

-0.70

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.5

REVEL

Benign

0.039

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.011

Vest4

0.26

MutPred

0.39

Loss of sheet (P = 0.0181);

MVP

0.60

MPC

0.18

ClinPred

0.084

GERP RS

0.70

Varity_R

0.26

gMVP

0.091

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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X-134852859-T-G

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