X-12614847-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001368397.1(FRMPD4):c.388G>A(p.Ala130Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00087 in 1,181,909 control chromosomes in the GnomAD database, including 1 homozygotes. There are 339 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., 32 hem., cov: 22)

Exomes 𝑓: 0.00086 ( 1 hom. 307 hem. )

Consequence

FRMPD4
NM_001368397.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.76

Publications

5 publications found

Variant links:

Genes affected

FRMPD4 (HGNC:29007): (FERM and PDZ domain containing 4) This gene encodes a multi-domain (WW, PDZ, FERM) containing protein. Through its interaction with other proteins (such as PSD-95), it functions as a positive regulator of dendritic spine morphogenesis and density, and is required for the maintenance of excitatory synaptic transmission. [provided by RefSeq, Jan 2010]

FRMPD4 Gene-Disease associations (from GenCC):

X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, X-linked 104
Inheritance: XL Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

FRMPD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006225556).

BP6

Variant X-12614847-G-A is Benign according to our data. Variant chrX-12614847-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD4	NM_001368397.1 link	c.388G>A	p.Ala130Thr	missense_variant	Exon 4 of 17	ENST00000675598.1	NP_001355326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMPD4	ENST00000675598.1 link	c.388G>A	p.Ala130Thr	missense_variant	Exon 4 of 17		NM_001368397.1	ENSP00000502607.1		A0A6Q8PH73

Frequencies

GnomAD3 genomes

AF:

0.000990

AC:

110

AN:

111056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000328

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00418

Gnomad ASJ

AF:

0.00643

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000391

Gnomad FIN

AF:

0.000841

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000755

Gnomad OTH

AF:

0.00133

GnomAD2 exomes

AF:

0.000904

AC:

164

AN:

181428

AF XY:

0.000879

show subpopulations

Gnomad AFR exome

AF:

0.0000765

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00566

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000438

Gnomad NFE exome

AF:

0.000900

Gnomad OTH exome

AF:

0.00268

GnomAD4 exome

AF:

0.000857

AC:

918

AN:

1070799

Hom.:

Cov.:

AF XY:

0.000906

AC XY:

307

AN XY:

338745

show subpopulations

African (AFR)

AF:

0.0000771

AC:

AN:

25941

American (AMR)

AF:

0.00123

AC:

AN:

35072

Ashkenazi Jewish (ASJ)

AF:

0.00553

AC:

106

AN:

19170

East Asian (EAS)

AF:

0.00

AC:

AN:

29944

South Asian (SAS)

AF:

0.0000188

AC:

AN:

53171

European-Finnish (FIN)

AF:

0.000494

AC:

AN:

40482

Middle Eastern (MID)

AF:

0.000745

AC:

AN:

4025

European-Non Finnish (NFE)

AF:

0.000823

AC:

673

AN:

817883

Other (OTH)

AF:

0.00155

AC:

AN:

45111

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000990

AC:

110

AN:

111110

Hom.:

Cov.:

AF XY:

0.000961

AC XY:

AN XY:

33306

show subpopulations

African (AFR)

AF:

0.0000328

AC:

AN:

30533

American (AMR)

AF:

0.00418

AC:

AN:

10527

Ashkenazi Jewish (ASJ)

AF:

0.00643

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.000392

AC:

AN:

2549

European-Finnish (FIN)

AF:

0.000841

AC:

AN:

5942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000755

AC:

AN:

52966

Other (OTH)

AF:

0.00132

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00105

Hom.:

Bravo

AF:

0.00122

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.000873

AC:

106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 15, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.021

T;T

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0062

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.36

N;.

PhyloP100

3.8

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.050

N;.

REVEL

Benign

0.10

Sift

Benign

0.38

T;.

Sift4G

Benign

0.37

T;T

Polyphen

0.012

B;.

Vest4

0.17

MVP

0.40

MPC

0.88

ClinPred

0.0097

GERP RS

4.6

Varity_R

0.083

gMVP

0.33

Mutation Taster

=95/5

polymorphism (auto)

(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