dbSNP rs886038209: FRMPD4:p.Cys553Arg (chrX-12716116-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001368397.1(FRMPD4):c.1657T>C(p.Cys553Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000932 in 1,073,283 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C553Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 9.3e-7 ( 0 hom. 1 hem. )

Consequence

FRMPD4
NM_001368397.1 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.62

Publications

2 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-12716116-T-C is Pathogenic according to our data. Variant chrX-12716116-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 254683.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD4	NM_001368397.1 link	c.1657T>C	p.Cys553Arg	missense_variant	Exon 15 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.1657T>C	p.Cys553Arg	missense_variant	Exon 15 of 17		NM_001368397.1	ENSP00000502607.1		A0A6Q8PH73

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.32e-7

AC:

AN:

1073283

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

347057

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25710

American (AMR)

AF:

0.00

AC:

AN:

34160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18393

East Asian (EAS)

AF:

0.00

AC:

AN:

28876

South Asian (SAS)

AF:

0.00

AC:

AN:

52852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39133

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3982

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

825520

Other (OTH)

AF:

0.00

AC:

AN:

44657

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, X-linked 104

Pathogenic:2

Oct 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 20, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.0022

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

T;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.

PhyloP100

3.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.16

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.032

D;D

Polyphen

0.88

P;.

Vest4

0.85

MutPred

0.43

Gain of disorder (P = 0.0415);.;

MVP

0.44

MPC

0.52

ClinPred

0.93

GERP RS

5.5

Varity_R

0.97

gMVP

0.81

Mutation Taster

=42/58

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over