rs5977623

chrX-132078484-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194277.3(FRMD7):c.1533T>C(p.Ile511=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,207,818 control chromosomes in the GnomAD database, including 37,254 homozygotes. There are 114,136 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (4446 hom., 9557 hem., cov: 22)
  • Exomes 𝑓: 0.29 (32808 hom. 104579 hem.)
• Consequence: FRMD7 NM_194277.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.390

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant X-132078484-A-G is Benign according to our data. Variant chrX-132078484-A-G is described in ClinVar as [Benign]. Clinvar id is 263088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-132078484-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD7	NM_194277.3	c.1533T>C	p.Ile511=	synonymous_variant	12/12	ENST00000298542.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD7	ENST00000298542.9	c.1533T>C	p.Ile511=	synonymous_variant	12/12	1	NM_194277.3	P1
FRMD7	ENST00000464296.1	c.1488T>C	p.Ile496=	synonymous_variant	12/12	1
FRMD7	ENST00000370879.5	c.1173T>C	p.Ile391=	synonymous_variant	8/8	1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 34812 AN: 110084 Hom.: 4442 Cov.: 22 AF XY: 0.294 AC XY: 9523 AN XY: 32370

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.306

GnomAD3 exomes AF: 0.260 AC: 47497 AN: 182804 Hom.: 4504 AF XY: 0.260 AC XY: 17541 AN XY: 67498

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.205

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.291 AC: 319158 AN: 1097680 Hom.: 32808 Cov.: 32 AF XY: 0.288 AC XY: 104579 AN XY: 363080

Gnomad4 AFR exome AF: 0.439

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.0736

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.305

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.316 AC: 34838 AN: 110138 Hom.: 4446 Cov.: 22 AF XY: 0.295 AC XY: 9557 AN XY: 32434

Gnomad4 AFR AF: 0.428

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.0993

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.302

Alfa AF: 0.299 Hom.: 13460

Bravo AF: 0.313

EpiCase AF: 0.305

EpiControl AF: 0.303

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	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.68
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5977623; hg19: chrX-131212512; COSMIC: COSV53745121; COSMIC: COSV53745121;