X-132077946-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_194277.3(FRMD7):c.2071G>A(p.Glu691Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FRMD7 NM_194277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD7	NM_194277.3	c.2071G>A	p.Glu691Lys	missense_variant	12/12	ENST00000298542.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD7	ENST00000298542.9	c.2071G>A	p.Glu691Lys	missense_variant	12/12	1	NM_194277.3	P1
FRMD7	ENST00000464296.1	c.2026G>A	p.Glu676Lys	missense_variant	12/12	1
FRMD7	ENST00000370879.5	c.1711G>A	p.Glu571Lys	missense_variant	8/8	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 19, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 691 of the FRMD7 protein (p.Glu691Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FRMD7-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	22
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Uncertain	0.56	D
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.99, 0.99	.;D;D
Vest4		0.47
MutPred		0.29		.;Gain of ubiquitination at E691 (P = 0.0031);.;
MVP		0.93
MPC		0.92
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.63
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-131211974;