X-12716641-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001368395.3(FRMPD4):c.2293G>C(p.Ala765Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,207,979 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A765T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000012 ( 0 hom. 5 hem. )

Consequence

FRMPD4
NM_001368395.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.350

Publications

3 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041328937).

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368395.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FRMPD4	NM_001368397.1	MANE Select	c.2182G>C	p.Ala728Pro	missense	Exon 15 of 17	NP_001355326.1
FRMPD4	NM_001368395.3		c.2293G>C	p.Ala765Pro	missense	Exon 17 of 19	NP_001355324.1
FRMPD4	NM_001368396.3		c.2188G>C	p.Ala730Pro	missense	Exon 15 of 17	NP_001355325.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FRMPD4	ENST00000675598.1	MANE Select	c.2182G>C	p.Ala728Pro	missense	Exon 15 of 17	ENSP00000502607.1
FRMPD4	ENST00000380682.5	TSL:1	c.2182G>C	p.Ala728Pro	missense	Exon 15 of 17	ENSP00000370057.1
FRMPD4	ENST00000656302.1		c.2236G>C	p.Ala746Pro	missense	Exon 17 of 19	ENSP00000499481.1

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111659

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183415

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1096320

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361708

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26383

American (AMR)

AF:

0.0000568

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19375

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

840339

Other (OTH)

AF:

0.0000217

AC:

AN:

46046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

AF:

0.00000896

AC:

AN:

111659

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33829

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30714

American (AMR)

AF:

0.00

AC:

AN:

10570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3553

South Asian (SAS)

AF:

0.00

AC:

AN:

2635

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6019

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53096

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, X-linked 104 (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.10

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.029

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.82

M_CAP

Benign

0.0051

MetaRNN

Benign

0.041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.35

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.14

REVEL

Benign

0.014

Sift

Benign

0.35

Sift4G

Benign

0.23

Polyphen

0.0010

Vest4

0.15

MVP

0.068

MPC

0.16

ClinPred

0.066

GERP RS

-1.8

Varity_R

0.064

gMVP

0.42

Mutation Taster

=93/7

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over