rs6637934

Variant names:

• chrX-132078614-C-T
• rs6637934
• NM_194277.3:c.1403G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194277.3(FRMD7):​c.1403G>A​(p.Arg468His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0581 in 1,208,945 control chromosomes in the GnomAD database, including 1,507 homozygotes. There are 22,909 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R468C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.059 (158 hom., 1835 hem., cov: 22)
  • Exomes 𝑓: 0.058 (1349 hom. 21074 hem.)
• Consequence: FRMD7 NM_194277.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.418
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• nystagmus 1, congenital, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013616383).
• BP6: Variant X-132078614-C-T is Benign according to our data. Variant chrX-132078614-C-T is described in ClinVar as Benign. ClinVar VariationId is 263087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD7	NM_194277.3	c.1403G>A	p.Arg468His	missense_variant	Exon 12 of 12	ENST00000298542.9	NP_919253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD7	ENST00000298542.9	c.1403G>A	p.Arg468His	missense_variant	Exon 12 of 12	1	NM_194277.3	ENSP00000298542.3
FRMD7	ENST00000464296.1	c.1358G>A	p.Arg453His	missense_variant	Exon 12 of 12	1		ENSP00000417996.1
FRMD7	ENST00000370879.5	c.1043G>A	p.Arg348His	missense_variant	Exon 8 of 8	1		ENSP00000359916.1

Frequencies

GnomAD3 genomes AF: 0.0588 AC: 6567 AN: 111629 Hom.: 156 Cov.: 22

Gnomad AFR AF: 0.0733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.0950

Gnomad EAS AF: 0.0982

Gnomad SAS AF: 0.0707

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0591

Gnomad NFE AF: 0.0558

Gnomad OTH AF: 0.0498

GnomAD2 exomes AF: 0.0562 AC: 10268 AN: 182862 AF XY: 0.0582

Gnomad AFR exome AF: 0.0757

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.0778

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.0450

Gnomad NFE exome AF: 0.0565

Gnomad OTH exome AF: 0.0598

GnomAD4 exome AF: 0.0580 AC: 63652 AN: 1097261 Hom.: 1349 Cov.: 32 AF XY: 0.0581 AC XY: 21074 AN XY: 362653

African (AFR) AF: 0.0791 AC: 2086 AN: 26382

American (AMR) AF: 0.0171 AC: 602 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.0795 AC: 1541 AN: 19382

East Asian (EAS) AF: 0.0732 AC: 2212 AN: 30202

South Asian (SAS) AF: 0.0690 AC: 3735 AN: 54126

European-Finnish (FIN) AF: 0.0452 AC: 1830 AN: 40527

Middle Eastern (MID) AF: 0.0800 AC: 331 AN: 4136

European-Non Finnish (NFE) AF: 0.0574 AC: 48318 AN: 841232

Other (OTH) AF: 0.0651 AC: 2997 AN: 46069

GnomAD4 genome AF: 0.0588 AC: 6568 AN: 111684 Hom.: 158 Cov.: 22 AF XY: 0.0541 AC XY: 1835 AN XY: 33908

African (AFR) AF: 0.0734 AC: 2256 AN: 30730

American (AMR) AF: 0.0243 AC: 255 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 251 AN: 2642

East Asian (EAS) AF: 0.0969 AC: 342 AN: 3531

South Asian (SAS) AF: 0.0716 AC: 192 AN: 2680

European-Finnish (FIN) AF: 0.0366 AC: 221 AN: 6046

Middle Eastern (MID) AF: 0.0556 AC: 12 AN: 216

European-Non Finnish (NFE) AF: 0.0558 AC: 2964 AN: 53118

Other (OTH) AF: 0.0492 AC: 75 AN: 1525

Alfa AF: 0.0585 Hom.: 5720

Bravo AF: 0.0583

TwinsUK AF: 0.0636 AC: 236

ALSPAC AF: 0.0613 AC: 177

ESP6500AA AF: 0.0754 AC: 289

ESP6500EA AF: 0.0572 AC: 385

ExAC AF: 0.0594 AC: 7216

EpiCase AF: 0.0554

EpiControl AF: 0.0567

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nystagmus 1, congenital, X-linked Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	.;T;.
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.0	.;N;.
PhyloP100		0.42
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.3	N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.64, 0.75	.;P;P
Vest4		0.028
MPC		0.36
ClinPred		0.017	T
GERP RS		4.9
Varity_R		0.14
gMVP		0.20
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6637934; hg19: chrX-131212642; COSMIC: COSV53746721; COSMIC: COSV53746721;