rs5977625

chrX-132082426-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. S281S) has been classified 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.54

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]

ACMG classification

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	UniProt
FRMD7	NM_194277.3	c.842C>T	p.Ser281Leu	missense_variant	9/12	ENST00000298542.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD7	ENST00000298542.9	c.842C>T	p.Ser281Leu	missense_variant	9/12	1	NM_194277.3	P1
FRMD7	ENST00000464296.1	c.797C>T	p.Ser266Leu	missense_variant	9/12	1
FRMD7	ENST00000370879.5	c.482C>T	p.Ser161Leu	missense_variant	5/8	1

Frequencies

GnomAD3 genomes AF: 0.0638 AC: 7147 AN: 112028 Hom.: 237 Cov.: 23 AF XY: 0.0586 AC XY: 2006 AN XY: 34216

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

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.: 30 AF XY: 0.0410 AC XY: 14823 AN XY: 361743

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.: 23 AF XY: 0.0587 AC XY: 2013 AN XY: 34279

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	0.00043	P;P;P
PrimateAI	Uncertain	0.64	T
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	T
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

Other links and lift over

dbSNP: rs5977625; hg19: chrX-131216454; COSMIC: COSV53745449;