chrX-132077930-T-C

Position:

• chrX-132077930-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_194277.3(FRMD7):​c.2087A>G​(p.Asn696Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,582 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: FRMD7 NM_194277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.604

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044550717).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRMD7	NM_194277.3	c.2087A>G	p.Asn696Ser	missense_variant	12/12	ENST00000298542.9	NP_919253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRMD7	ENST00000298542.9	c.2087A>G	p.Asn696Ser	missense_variant	12/12	1	NM_194277.3	ENSP00000298542.3
FRMD7	ENST00000464296.1	c.2042A>G	p.Asn681Ser	missense_variant	12/12	1		ENSP00000417996.1
FRMD7	ENST00000370879.5	c.1727A>G	p.Asn576Ser	missense_variant	8/8	1		ENSP00000359916.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097582 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 362970

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with FRMD7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 696 of the FRMD7 protein (p.Asn696Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.14
DANN	Benign	0.76
DEOGEN2	Benign	0.0047	.;T;.
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.045	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.55	.;N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.18	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.0, 0.0020	.;B;B
Vest4		0.032
MutPred		0.21		.;Loss of catalytic residue at N696 (P = 9e-04);.;
MVP		0.47
MPC		0.19
ClinPred		0.030	T
GERP RS		-5.6
Varity_R		0.026
gMVP		0.046

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-131211958;