X-132077903-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_194277.3(FRMD7):c.2114C>T(p.Ser705Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,095,995 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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: 0.0000046 (0 hom. 1 hem.)
• Consequence: FRMD7 NM_194277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0480088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD7	NM_194277.3	c.2114C>T	p.Ser705Leu	missense_variant	12/12	ENST00000298542.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD7	ENST00000298542.9	c.2114C>T	p.Ser705Leu	missense_variant	12/12	1	NM_194277.3	P1
FRMD7	ENST00000464296.1	c.2069C>T	p.Ser690Leu	missense_variant	12/12	1
FRMD7	ENST00000370879.5	c.1754C>T	p.Ser585Leu	missense_variant	8/8	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 182814 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67522

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1095995 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 1 AN XY: 361427

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000142

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: 0.00

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

Invitae

Sep 01, 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 leucine 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 present in population databases (no rsID available, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 705 of the FRMD7 protein (p.Ser705Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	5.8
Dann	Benign	0.90
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.40	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.13
MutPred		0.23		.;Loss of relative solvent accessibility (P = 0.0186);.;
MVP		0.37
MPC		0.21
ClinPred		0.027	T
GERP RS		3.3
Varity_R		0.048
gMVP		0.13

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: rs1259890351; hg19: chrX-131211931;