rs6637934

Variant names:

• chrX-132078614-C-T
• rs6637934
• NM_194277.3:c.1403G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194277.3(FRMD7):​c.1403G>A​(p.Arg468His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0581 in 1,208,945 control chromosomes in the GnomAD database, including 1,507 homozygotes. There are 22,909 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R468C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.059 (158 hom., 1835 hem., cov: 22)
  • Exomes 𝑓: 0.058 (1349 hom. 21074 hem.)
• Consequence: FRMD7 NM_194277.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.418
• Publications: 19 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013616383).
• BP6: Variant X-132078614-C-T is Benign according to our data. Variant chrX-132078614-C-T is described in ClinVar as Benign. ClinVar VariationId is 263087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

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.1403G>A	p.Arg468His	missense	Exon 12 of 12	NP_919253.1	Q6ZUT3-1
	FRMD7	NM_001306193.2		c.1358G>A	p.Arg453His	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.1403G>A	p.Arg468His	missense	Exon 12 of 12	ENSP00000298542.3	Q6ZUT3-1
	FRMD7	ENST00000464296.1	TSL:1	c.1358G>A	p.Arg453His	missense	Exon 12 of 12	ENSP00000417996.1	Q6ZUT3-2
	FRMD7	ENST00000370879.5	TSL:1	c.1043G>A	p.Arg348His	missense	Exon 8 of 8	ENSP00000359916.1	X6R7S7

Frequencies

GnomAD3 genomes AF: 0.0588 AC: 6567 AN: 111629 Hom.: 156 Cov.: 22

Gnomad AFR AF: 0.0733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.0950

Gnomad EAS AF: 0.0982

Gnomad SAS AF: 0.0707

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0591

Gnomad NFE AF: 0.0558

Gnomad OTH AF: 0.0498

GnomAD2 exomes AF: 0.0562 AC: 10268 AN: 182862 AF XY: 0.0582

Gnomad AFR exome AF: 0.0757

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.0778

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.0450

Gnomad NFE exome AF: 0.0565

Gnomad OTH exome AF: 0.0598

GnomAD4 exome AF: 0.0580 AC: 63652 AN: 1097261 Hom.: 1349 Cov.: 32 AF XY: 0.0581 AC XY: 21074 AN XY: 362653

African (AFR) AF: 0.0791 AC: 2086 AN: 26382

American (AMR) AF: 0.0171 AC: 602 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.0795 AC: 1541 AN: 19382

East Asian (EAS) AF: 0.0732 AC: 2212 AN: 30202

South Asian (SAS) AF: 0.0690 AC: 3735 AN: 54126

European-Finnish (FIN) AF: 0.0452 AC: 1830 AN: 40527

Middle Eastern (MID) AF: 0.0800 AC: 331 AN: 4136

European-Non Finnish (NFE) AF: 0.0574 AC: 48318 AN: 841232

Other (OTH) AF: 0.0651 AC: 2997 AN: 46069

GnomAD4 genome AF: 0.0588 AC: 6568 AN: 111684 Hom.: 158 Cov.: 22 AF XY: 0.0541 AC XY: 1835 AN XY: 33908

African (AFR) AF: 0.0734 AC: 2256 AN: 30730

American (AMR) AF: 0.0243 AC: 255 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 251 AN: 2642

East Asian (EAS) AF: 0.0969 AC: 342 AN: 3531

South Asian (SAS) AF: 0.0716 AC: 192 AN: 2680

European-Finnish (FIN) AF: 0.0366 AC: 221 AN: 6046

Middle Eastern (MID) AF: 0.0556 AC: 12 AN: 216

European-Non Finnish (NFE) AF: 0.0558 AC: 2964 AN: 53118

Other (OTH) AF: 0.0492 AC: 75 AN: 1525

Alfa AF: 0.0585 Hom.: 5720

Bravo AF: 0.0583

TwinsUK AF: 0.0636 AC: 236

ALSPAC AF: 0.0613 AC: 177

ESP6500AA AF: 0.0754 AC: 289

ESP6500EA AF: 0.0572 AC: 385

ExAC AF: 0.0594 AC: 7216

EpiCase AF: 0.0554

EpiControl AF: 0.0567

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Nystagmus 1, congenital, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.42
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.3	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.14	T
Polyphen		0.64	P
Vest4		0.028
MPC		0.36
ClinPred		0.017	T
GERP RS		4.9
Varity_R		0.14
gMVP		0.20
Mutation Taster		=97/3	polymorphism (auto)

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

dbSNP: rs6637934; hg19: chrX-131212642; COSMIC: COSV53746721; COSMIC: COSV53746721;