X-132084546-G-A

Variant names:

• chrX-132084546-G-A
• rs137852212
• NM_194277.3:c.685C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_194277.3(FRMD7):​c.685C>T​(p.Arg229Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000935 in 1,069,638 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: FRMD7 NM_194277.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.00

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 9 ACMG points.

• PM1: In a domain FERM (size 280) in uniprot entity FRMD7_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_194277.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant X-132084546-G-A is Pathogenic according to our data. Variant chrX-132084546-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449483.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD7	NM_194277.3	c.685C>T	p.Arg229Cys	missense_variant	Exon 8 of 12	ENST00000298542.9	NP_919253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD7	ENST00000298542.9	c.685C>T	p.Arg229Cys	missense_variant	Exon 8 of 12	1	NM_194277.3	ENSP00000298542.3
FRMD7	ENST00000464296.1	c.640C>T	p.Arg214Cys	missense_variant	Exon 8 of 12	1		ENSP00000417996.1
FRMD7	ENST00000370879.5	c.325C>T	p.Arg109Cys	missense_variant	Exon 4 of 8	1		ENSP00000359916.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.35e-7 AC: 1 AN: 1069638 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 338944

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: 0.00000123

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 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. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 229 of the FRMD7 protein (p.Arg229Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital motor nystagmus (PMID: 17768376, 28623544). ClinVar contains an entry for this variant (Variation ID: 449483). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FRMD7 function (PMID: 23406872). This variant disrupts the p.Arg229 amino acid residue in FRMD7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17962394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2021	Published functional studies demonstrate a damaging effect with reduced R229C mutant protein expression, as compared to wild-type, and dominant-negative inhibition of neurite outgrowth (Watkins et al., 2013); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17768376, 23406872, 28623544, 19072571, 27535533, 21904664) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	.;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.3	.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.9	D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.87
MutPred		0.89		.;Gain of methylation at K230 (P = 0.037);.;
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.79

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: rs137852212; hg19: chrX-131218574; COSMIC: COSV53747620;