ENST00000464296.1:c.207G>A

Variant names:

• chrX-132097298-C-T
• rs137852209
• ENST00000464296.1:c.207G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. 11/19 in silico tools predict 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
• 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: Uncertain_significance. The variant received 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 VariationId is 10785.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000464296.1. 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.252G>A	p.Val84Val	synonymous	Exon 4 of 12	NP_919253.1	Q6ZUT3-1
	FRMD7	NM_001306193.2		c.207G>A	p.Met69Ile	missense splice_region	Exon 4 of 12	NP_001293122.1	Q6ZUT3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD7	ENST00000464296.1	TSL:1	c.207G>A	p.Met69Ile	missense splice_region	Exon 4 of 12	ENSP00000417996.1	Q6ZUT3-2
	FRMD7	ENST00000298542.9	TSL:1 MANE Select	c.252G>A	p.Val84Val	synonymous	Exon 4 of 12	ENSP00000298542.3	Q6ZUT3-1

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

African (AFR) AF: 0.00 AC: 0 AN: 26110

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19287

East Asian (EAS) AF: 0.00 AC: 0 AN: 30155

South Asian (SAS) AF: 0.00 AC: 0 AN: 53792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4105

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 828251

Other (OTH) AF: 0.00 AC: 0 AN: 45600

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Nystagmus 1, congenital, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
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
PhyloP100		3.3
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
Mutation Taster		=27/73	disease causing (ClinVar)

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

Other links and lift over

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