rs786205896

Positions:

• chrX-132085670-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The ENST00000298542.9(FRMD7):​c.556A>G​(p.Met186Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M186T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: FRMD7 ENST00000298542.9 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.24

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant X-132085670-T-C is Pathogenic according to our data. Variant chrX-132085670-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 192295.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMD7	NM_194277.3	c.556A>G	p.Met186Val	missense_variant	7/12	ENST00000298542.9	NP_919253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMD7	ENST00000298542.9	c.556A>G	p.Met186Val	missense_variant	7/12	1	NM_194277.3	ENSP00000298542	P1
FRMD7	ENST00000464296.1	c.511A>G	p.Met171Val	missense_variant	7/12	1		ENSP00000417996
FRMD7	ENST00000370879.5	c.196A>G	p.Met66Val	missense_variant	3/8	1		ENSP00000359916

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nystagmus 1, congenital, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Mutsuddi Laboratory, Department of Molecular and Human Genetics, Banaras Hindu University

Jan 01, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	.;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.5	.;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.96, 0.89	.;D;P
Vest4		0.89
MutPred		0.69		.;Loss of sheet (P = 0.0817);.;
MVP		0.95
MPC		0.86
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.85

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: rs786205896; hg19: chrX-131219698;