rs144170600

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.2599A>G(p.Asn867Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000382 in 1,206,761 control chromosomes in the GnomAD database, including 1 homozygotes. There are 220 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00040 ( 1 hom. 211 hem. )

Consequence

FRMPD4
NM_001368397.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.65

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=0.0034191012).

BP6

Variant X-12717058-A-G is Benign according to our data. Variant chrX-12717058-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD4	NM_001368397.1 link	c.2599A>G	p.Asn867Asp	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.2599A>G	p.Asn867Asp	missense_variant	Exon 15 of 17		NM_001368397.1	ENSP00000502607.1

Frequencies

GnomAD3 genomes

AF:

0.000239

AC:

AN:

112828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000928

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00328

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.000281

Gnomad OTH

AF:

0.000657

GnomAD2 exomes

AF:

0.000664

AC:

120

AN:

180770

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000184

Gnomad ASJ exome

AF:

0.000408

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000398

Gnomad OTH exome

AF:

0.000670

GnomAD4 exome

AF:

0.000398

AC:

435

AN:

1093882

Hom.:

Cov.:

AF XY:

0.000587

AC XY:

211

AN XY:

359528

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26333

American (AMR)

AF:

0.000142

AC:

AN:

35097

Ashkenazi Jewish (ASJ)

AF:

0.000776

AC:

AN:

19331

East Asian (EAS)

AF:

0.00

AC:

AN:

30103

South Asian (SAS)

AF:

0.00359

AC:

194

AN:

53968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40367

Middle Eastern (MID)

AF:

0.00291

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.000215

AC:

180

AN:

838656

Other (OTH)

AF:

0.000610

AC:

AN:

45907

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.000230

AC:

AN:

112879

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

AN XY:

35033

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31149

American (AMR)

AF:

0.0000927

AC:

AN:

10790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00292

AC:

AN:

2738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6231

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000281

AC:

AN:

53300

Other (OTH)

AF:

0.000649

AC:

AN:

1542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.000385

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.000906

AC:

110

EpiCase

AF:

0.000493

EpiControl

AF:

0.000653

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Nov 16, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intellectual disability, X-linked 104

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FRMPD4-related disorder

Benign:1

Aug 09, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.90

BayesDel_noAF

Benign

-1.1

CADD

Benign

7.8

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.026

T;T

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.50

N;.

PhyloP100

3.6

PrimateAI

Benign

0.29

PROVEAN

Benign

1.8

N;.

REVEL

Benign

0.13

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Vest4

0.055

ClinPred

0.0094

GERP RS

2.3

Varity_R

0.049

gMVP

0.23

Mutation Taster

=97/3

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