rs5930546

Variant names:

• chrX-132100705-G-A
• rs5930546
• NM_194277.3:c.69C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194277.3(FRMD7):​c.69C>T​(p.Ser23Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0984 in 1,194,992 control chromosomes in the GnomAD database, including 4,326 homozygotes. There are 37,694 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (361 hom., 2700 hem., cov: 23)
  • Exomes 𝑓: 0.10 (3965 hom. 34994 hem.)
• Consequence: FRMD7 NM_194277.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.727
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-132100705-G-A is Benign according to our data. Variant chrX-132100705-G-A is described in ClinVar as Benign. ClinVar VariationId is 263089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.727 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD7	NM_194277.3	c.69C>T	p.Ser23Ser	synonymous_variant	Exon 2 of 12	ENST00000298542.9	NP_919253.1
FRMD7	NM_001306193.2	c.69C>T	p.Ser23Ser	synonymous_variant	Exon 2 of 12		NP_001293122.1
FRMD7	XM_017029947.3	c.21C>T	p.Ser7Ser	synonymous_variant	Exon 2 of 12		XP_016885436.1
FRMD7	XM_017029948.3	c.30-6566C>T		intron_variant	Intron 1 of 8		XP_016885437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD7	ENST00000298542.9	c.69C>T	p.Ser23Ser	synonymous_variant	Exon 2 of 12	1	NM_194277.3	ENSP00000298542.3
FRMD7	ENST00000464296.1	c.69C>T	p.Ser23Ser	synonymous_variant	Exon 2 of 12	1		ENSP00000417996.1
FRMD7	ENST00000687717.1	n.327C>T		non_coding_transcript_exon_variant	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0836 AC: 9334 AN: 111596 Hom.: 361 Cov.: 23

Gnomad AFR AF: 0.0587

Gnomad AMI AF: 0.0613

Gnomad AMR AF: 0.0465

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.00168

Gnomad SAS AF: 0.0832

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0894

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0868

GnomAD2 exomes AF: 0.0840 AC: 15323 AN: 182485 AF XY: 0.0869

Gnomad AFR exome AF: 0.0580

Gnomad AMR exome AF: 0.0384

Gnomad ASJ exome AF: 0.0981

Gnomad EAS exome AF: 0.000650

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0939

GnomAD4 exome AF: 0.100 AC: 108292 AN: 1083347 Hom.: 3965 Cov.: 28 AF XY: 0.0998 AC XY: 34994 AN XY: 350707

African (AFR) AF: 0.0570 AC: 1490 AN: 26146

American (AMR) AF: 0.0397 AC: 1397 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 1968 AN: 19287

East Asian (EAS) AF: 0.000332 AC: 10 AN: 30159

South Asian (SAS) AF: 0.0924 AC: 4971 AN: 53824

European-Finnish (FIN) AF: 0.117 AC: 4692 AN: 39999

Middle Eastern (MID) AF: 0.0943 AC: 387 AN: 4102

European-Non Finnish (NFE) AF: 0.108 AC: 89378 AN: 828973

Other (OTH) AF: 0.0876 AC: 3999 AN: 45664

GnomAD4 genome AF: 0.0836 AC: 9337 AN: 111645 Hom.: 361 Cov.: 23 AF XY: 0.0797 AC XY: 2700 AN XY: 33859

African (AFR) AF: 0.0588 AC: 1808 AN: 30733

American (AMR) AF: 0.0464 AC: 491 AN: 10582

Ashkenazi Jewish (ASJ) AF: 0.0873 AC: 231 AN: 2645

East Asian (EAS) AF: 0.00169 AC: 6 AN: 3553

South Asian (SAS) AF: 0.0835 AC: 225 AN: 2696

European-Finnish (FIN) AF: 0.108 AC: 651 AN: 6024

Middle Eastern (MID) AF: 0.0849 AC: 18 AN: 212

European-Non Finnish (NFE) AF: 0.108 AC: 5735 AN: 52999

Other (OTH) AF: 0.0858 AC: 130 AN: 1516

Alfa AF: 0.0961 Hom.: 4882

Bravo AF: 0.0772

EpiCase AF: 0.109

EpiControl AF: 0.102

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

- -

Nystagmus 1, congenital, X-linked Benign:2

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. -

Aug 10, 2021

Genome-Nilou Lab

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.055
DANN	Benign	0.66
PhyloP100		-0.73
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs5930546; hg19: chrX-131234733;