rs2276293

Positions:

• chr11-77206175-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000260.4(MYO7A):​c.5715A>G​(p.Lys1905=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 1,611,312 control chromosomes in the GnomAD database, including 200,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24425 hom., cov: 31)
  • Exomes 𝑓: 0.49 (176321 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.16

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 11-77206175-A-G is Benign according to our data. Variant chr11-77206175-A-G is described in ClinVar as [Benign]. Clinvar id is 43296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77206175-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.5715A>G	p.Lys1905=	synonymous_variant	41/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.5715A>G	p.Lys1905=	synonymous_variant	41/49	1	NM_000260.4

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84647 AN: 151796 Hom.: 24373 Cov.: 31

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.481

Gnomad OTH AF: 0.540

GnomAD3 exomes AF: 0.516 AC: 127132 AN: 246242 Hom.: 33918 AF XY: 0.502 AC XY: 67091 AN XY: 133568

Gnomad AFR exome AF: 0.706

Gnomad AMR exome AF: 0.641

Gnomad ASJ exome AF: 0.429

Gnomad EAS exome AF: 0.509

Gnomad SAS exome AF: 0.391

Gnomad FIN exome AF: 0.594

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.488 AC: 711550 AN: 1459398 Hom.: 176321 Cov.: 39 AF XY: 0.483 AC XY: 350887 AN XY: 725886

Gnomad4 AFR exome AF: 0.706

Gnomad4 AMR exome AF: 0.634

Gnomad4 ASJ exome AF: 0.420

Gnomad4 EAS exome AF: 0.483

Gnomad4 SAS exome AF: 0.396

Gnomad4 FIN exome AF: 0.594

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.482

GnomAD4 genome AF: 0.558 AC: 84766 AN: 151914 Hom.: 24425 Cov.: 31 AF XY: 0.561 AC XY: 41613 AN XY: 74234

Gnomad4 AFR AF: 0.704

Gnomad4 AMR AF: 0.588

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.492

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.603

Gnomad4 NFE AF: 0.481

Gnomad4 OTH AF: 0.540

Alfa AF: 0.500 Hom.: 26544

Bravo AF: 0.566

Asia WGS AF: 0.452 AC: 1570 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 08, 2007	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Usher syndrome type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Usher syndrome type 1B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.7
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs2276293; hg19: chr11-76917220; COSMIC: COSV68683630; COSMIC: COSV68683630;