rs137852209

Positions:

• chrX-132097298-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000464296.1(FRMD7):​c.207G>A​(p.Met69Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000923 in 1,083,026 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: FRMD7 ENST00000464296.1 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.28

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-132097298-C-T is Pathogenic according to our data. Variant chrX-132097298-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10785.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMD7	NM_194277.3	c.252G>A	p.Val84=	synonymous_variant	4/12	ENST00000298542.9	NP_919253.1
FRMD7	NM_001306193.2	c.207G>A	p.Met69Ile	missense_variant, splice_region_variant	4/12		NP_001293122.1
FRMD7	XM_017029947.3	c.204G>A	p.Val68=	synonymous_variant	4/12		XP_016885436.1
FRMD7	XM_017029948.3	c.30-3159G>A		intron_variant			XP_016885437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMD7	ENST00000464296.1	c.207G>A	p.Met69Ile	missense_variant, splice_region_variant	4/12	1		ENSP00000417996
FRMD7	ENST00000298542.9	c.252G>A	p.Val84=	synonymous_variant	4/12	1	NM_194277.3	ENSP00000298542	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.23e-7 AC: 1 AN: 1083026 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 350210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000121

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Nystagmus 1, congenital, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Benign	0.96
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	0.000045	A;A
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.14
Sift	Benign	0.32	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.45
MutPred		0.45		Gain of catalytic residue at P71 (P = 0.0282);
MVP		0.82
ClinPred		0.52	D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852209; hg19: chrX-131231326; COSMIC: COSV104539633; COSMIC: COSV104539633;