rs5977623

Variant names:

• chrX-132078484-A-G
• rs5977623
• NM_194277.3:c.1533T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000298542.9(FRMD7):​c.1533T>C​(p.Ile511Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,207,818 control chromosomes in the GnomAD database, including 37,254 homozygotes. There are 114,136 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (4446 hom., 9557 hem., cov: 22)
  • Exomes 𝑓: 0.29 (32808 hom. 104579 hem.)
• Consequence: FRMD7 ENST00000298542.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.390
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant X-132078484-A-G is Benign according to our data. Variant chrX-132078484-A-G is described in ClinVar as Benign. ClinVar VariationId is 263088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000298542.9. 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.1533T>C	p.Ile511Ile	synonymous	Exon 12 of 12	NP_919253.1
	FRMD7	NM_001306193.2		c.1488T>C	p.Ile496Ile	synonymous	Exon 12 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.1533T>C	p.Ile511Ile	synonymous	Exon 12 of 12	ENSP00000298542.3
	FRMD7	ENST00000464296.1	TSL:1	c.1488T>C	p.Ile496Ile	synonymous	Exon 12 of 12	ENSP00000417996.1
	FRMD7	ENST00000370879.5	TSL:1	c.1173T>C	p.Ile391Ile	synonymous	Exon 8 of 8	ENSP00000359916.1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 34812 AN: 110084 Hom.: 4442 Cov.: 22

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.306

GnomAD2 exomes AF: 0.260 AC: 47497 AN: 182804 AF XY: 0.260

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.291 AC: 319158 AN: 1097680 Hom.: 32808 Cov.: 32 AF XY: 0.288 AC XY: 104579 AN XY: 363080

African (AFR) AF: 0.439 AC: 11584 AN: 26395

American (AMR) AF: 0.125 AC: 4388 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 5741 AN: 19383

East Asian (EAS) AF: 0.0736 AC: 2222 AN: 30198

South Asian (SAS) AF: 0.210 AC: 11357 AN: 54139

European-Finnish (FIN) AF: 0.301 AC: 12214 AN: 40521

Middle Eastern (MID) AF: 0.394 AC: 1629 AN: 4134

European-Non Finnish (NFE) AF: 0.305 AC: 256614 AN: 841621

Other (OTH) AF: 0.291 AC: 13409 AN: 46085

GnomAD4 genome AF: 0.316 AC: 34838 AN: 110138 Hom.: 4446 Cov.: 22 AF XY: 0.295 AC XY: 9557 AN XY: 32434

African (AFR) AF: 0.428 AC: 12932 AN: 30182

American (AMR) AF: 0.169 AC: 1745 AN: 10345

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 798 AN: 2622

East Asian (EAS) AF: 0.0993 AC: 347 AN: 3496

South Asian (SAS) AF: 0.198 AC: 509 AN: 2576

European-Finnish (FIN) AF: 0.286 AC: 1662 AN: 5803

Middle Eastern (MID) AF: 0.355 AC: 75 AN: 211

European-Non Finnish (NFE) AF: 0.308 AC: 16224 AN: 52721

Other (OTH) AF: 0.302 AC: 455 AN: 1505

Alfa AF: 0.302 Hom.: 17661

Bravo AF: 0.313

EpiCase AF: 0.305

EpiControl AF: 0.303

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
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.68
DANN	Benign	0.70
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5977623; hg19: chrX-131212512; COSMIC: COSV53745121; COSMIC: COSV53745121;