chrX-132077946-C-T

Variant names:

• chrX-132077946-C-T
• NM_194277.3:c.2071G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD7	NM_194277.3	MANE Select	c.2071G>A	p.Glu691Lys	missense	Exon 12 of 12	NP_919253.1	Q6ZUT3-1
	FRMD7	NM_001306193.2		c.2026G>A	p.Glu676Lys	missense	Exon 12 of 12	NP_001293122.1	Q6ZUT3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD7	ENST00000298542.9	TSL:1 MANE Select	c.2071G>A	p.Glu691Lys	missense	Exon 12 of 12	ENSP00000298542.3	Q6ZUT3-1
	FRMD7	ENST00000464296.1	TSL:1	c.2026G>A	p.Glu676Lys	missense	Exon 12 of 12	ENSP00000417996.1	Q6ZUT3-2
	FRMD7	ENST00000370879.5	TSL:1	c.1711G>A	p.Glu571Lys	missense	Exon 8 of 8	ENSP00000359916.1	X6R7S7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.038	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.017	D
Polyphen		0.99	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
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

hg19: chrX-131211974;