rs5977625

Positions:

chrX-132082426-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_194277.3(FRMD7):c.842C>T(p.Ser281Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0434 in 1,208,380 control chromosomes in the GnomAD database, including 1,021 homozygotes. There are 16,836 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 236 hom., 2013 hem., cov: 23)

Exomes 𝑓: 0.041 ( 785 hom. 14823 hem. )

Consequence

FRMD7
NM_194277.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.54

Variant links:

Genes affected

FRMD7 (HGNC:8079): (FERM domain containing 7) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of neuron projection development. Predicted to act upstream of or within several processes, including negative regulation of stress fiber assembly; positive regulation of lamellipodium assembly; and positive regulation of small GTPase mediated signal transduction. Located in cytosol; nucleoplasm; and plasma membrane. Implicated in congenital nystagmus 1. [provided by Alliance of Genome Resources, Apr 2022]

FRMD7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022375286).

BP6

Variant X-132082426-G-A is Benign according to our data. Variant chrX-132082426-G-A is described in ClinVar as [Benign]. Clinvar id is 263090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-132082426-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMD7	NM_194277.3 linkuse as main transcript	c.842C>T	p.Ser281Leu	missense_variant	9/12	ENST00000298542.9	NP_919253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMD7	ENST00000298542.9 linkuse as main transcript	c.842C>T	p.Ser281Leu	missense_variant	9/12	1	NM_194277.3	ENSP00000298542	P1	Q6ZUT3-1
FRMD7	ENST00000464296.1 linkuse as main transcript	c.797C>T	p.Ser266Leu	missense_variant	9/12	1		ENSP00000417996		Q6ZUT3-2
FRMD7	ENST00000370879.5 linkuse as main transcript	c.482C>T	p.Ser161Leu	missense_variant	5/8	1		ENSP00000359916

Frequencies

GnomAD3 genomes

AF:

0.0638

AC:

7147

AN:

112028

Hom.:

237

Cov.:

AF XY:

0.0586

AC XY:

2006

AN XY:

34216

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.0541

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0712

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.0334

Gnomad FIN

AF:

0.0478

Gnomad MID

AF:

0.0975

Gnomad NFE

AF:

0.0450

Gnomad OTH

AF:

0.0535

GnomAD3 exomes

AF:

0.0441

AC:

8078

AN:

183238

Hom.:

164

AF XY:

0.0432

AC XY:

2928

AN XY:

67770

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.0211

Gnomad ASJ exome

AF:

0.0661

Gnomad EAS exome

AF:

0.000144

Gnomad SAS exome

AF:

0.0317

Gnomad FIN exome

AF:

0.0510

Gnomad NFE exome

AF:

0.0446

Gnomad OTH exome

AF:

0.0544

GnomAD4 exome

AF:

0.0413

AC:

45332

AN:

1096299

Hom.:

785

Cov.:

AF XY:

0.0410

AC XY:

14823

AN XY:

361743

show subpopulations

Gnomad4 AFR exome

AF:

0.124

Gnomad4 AMR exome

AF:

0.0229

Gnomad4 ASJ exome

AF:

0.0659

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.0331

Gnomad4 FIN exome

AF:

0.0550

Gnomad4 NFE exome

AF:

0.0395

Gnomad4 OTH exome

AF:

0.0505

GnomAD4 genome

AF:

0.0638

AC:

7152

AN:

112081

Hom.:

236

Cov.:

AF XY:

0.0587

AC XY:

2013

AN XY:

34279

show subpopulations

Gnomad4 AFR

AF:

0.120

Gnomad4 AMR

AF:

0.0326

Gnomad4 ASJ

AF:

0.0712

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.0331

Gnomad4 FIN

AF:

0.0478

Gnomad4 NFE

AF:

0.0450

Gnomad4 OTH

AF:

0.0528

Alfa

AF:

0.0461

Hom.:

2102

Bravo

AF:

0.0663

TwinsUK

AF:

0.0372

AC:

138

ALSPAC

AF:

0.0350

AC:

101

ESP6500AA

AF:

0.128

AC:

490

ESP6500EA

AF:

0.0412

AC:

277

ExAC

AF:

0.0473

AC:

5744

EpiCase

AF:

0.0431

EpiControl

AF:

0.0473

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nystagmus 1, congenital, X-linked

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.76

T;T;T

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.2

.;L;.

MutationTaster

Benign

0.00043

P;P;P

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.38

N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.67

T;T;T

Polyphen

1.0, 1.0

.;D;D

Vest4

0.099

MPC

0.82

ClinPred

0.0088

GERP RS

5.2

Varity_R

0.18

gMVP

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over