rs5977625

Variant names:

• chrX-132082426-G-A
• rs5977625
• NM_194277.3:c.842C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-132082426-G-A
• chrX-132082426-G-C

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.842C>T​(p.Ser281Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0434 in 1,208,380 control chromosomes in the GnomAD database, including 1,021 homozygotes. There are 16,836 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S281S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.064 (236 hom., 2013 hem., cov: 23)
  • Exomes 𝑓: 0.041 (785 hom. 14823 hem.)
• Consequence: FRMD7 NM_194277.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.54
• Publications: 13 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=0.0022375286).
• BP6: Variant X-132082426-G-A is Benign according to our data. Variant chrX-132082426-G-A is described in ClinVar as Benign. ClinVar VariationId is 263090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD7	NM_194277.3	MANE Select	c.842C>T	p.Ser281Leu	missense	Exon 9 of 12	NP_919253.1
	FRMD7	NM_001306193.2		c.797C>T	p.Ser266Leu	missense	Exon 9 of 12	NP_001293122.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD7	ENST00000298542.9	TSL:1 MANE Select	c.842C>T	p.Ser281Leu	missense	Exon 9 of 12	ENSP00000298542.3
	FRMD7	ENST00000464296.1	TSL:1	c.797C>T	p.Ser266Leu	missense	Exon 9 of 12	ENSP00000417996.1
	FRMD7	ENST00000370879.5	TSL:1	c.482C>T	p.Ser161Leu	missense	Exon 5 of 8	ENSP00000359916.1

Frequencies

GnomAD3 genomes AF: 0.0638 AC: 7147 AN: 112028 Hom.: 237 Cov.: 23

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.0541

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.0478

Gnomad MID AF: 0.0975

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0535

GnomAD2 exomes AF: 0.0441 AC: 8078 AN: 183238 AF XY: 0.0432

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0211

Gnomad ASJ exome AF: 0.0661

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.0510

Gnomad NFE exome AF: 0.0446

Gnomad OTH exome AF: 0.0544

GnomAD4 exome AF: 0.0413 AC: 45332 AN: 1096299 Hom.: 785 Cov.: 30 AF XY: 0.0410 AC XY: 14823 AN XY: 361743

African (AFR) AF: 0.124 AC: 3262 AN: 26364

American (AMR) AF: 0.0229 AC: 807 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.0659 AC: 1277 AN: 19371

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30194

South Asian (SAS) AF: 0.0331 AC: 1791 AN: 54099

European-Finnish (FIN) AF: 0.0550 AC: 2231 AN: 40530

Middle Eastern (MID) AF: 0.108 AC: 444 AN: 4098

European-Non Finnish (NFE) AF: 0.0395 AC: 33191 AN: 840401

Other (OTH) AF: 0.0505 AC: 2327 AN: 46037

GnomAD4 genome AF: 0.0638 AC: 7152 AN: 112081 Hom.: 236 Cov.: 23 AF XY: 0.0587 AC XY: 2013 AN XY: 34279

African (AFR) AF: 0.120 AC: 3700 AN: 30780

American (AMR) AF: 0.0326 AC: 346 AN: 10615

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 188 AN: 2641

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3563

South Asian (SAS) AF: 0.0331 AC: 89 AN: 2685

European-Finnish (FIN) AF: 0.0478 AC: 293 AN: 6130

Middle Eastern (MID) AF: 0.0977 AC: 21 AN: 215

European-Non Finnish (NFE) AF: 0.0450 AC: 2396 AN: 53235

Other (OTH) AF: 0.0528 AC: 81 AN: 1533

Alfa AF: 0.0524 Hom.: 2933

Bravo AF: 0.0663

TwinsUK AF: 0.0372 AC: 138

ALSPAC AF: 0.0350 AC: 101

ESP6500AA AF: 0.128 AC: 490

ESP6500EA AF: 0.0412 AC: 277

ExAC AF: 0.0473 AC: 5744

EpiCase AF: 0.0431

EpiControl AF: 0.0473

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Nystagmus 1, congenital, X-linked (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.34
Sift	Benign	0.19	T
Sift4G	Benign	0.67	T
Polyphen		1.0	D
Vest4		0.099
MPC		0.82
ClinPred		0.0088	T
GERP RS		5.2
Varity_R		0.18
gMVP		0.53
Mutation Taster		=93/7	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: rs5977625; hg19: chrX-131216454; COSMIC: COSV53745449;