rs45450893

chr11-77205600-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000260.4(MYO7A):c.5619G>A(p.Arg1873=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,613,468 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1873R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 32)
  • Exomes 𝑓: 0.022 (445 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.92

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 11-77205600-G-A is Benign according to our data. Variant chr11-77205600-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43293.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=1, Uncertain_significance=1}. Variant chr11-77205600-G-A is described in Lovd as [Benign]. Variant chr11-77205600-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0168 (2552/152296) while in subpopulation NFE AF= 0.027 (1833/68012). AF 95% confidence interval is 0.0259. There are 33 homozygotes in gnomad4. There are 1207 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.5619G>A	p.Arg1873=	synonymous_variant	40/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.5619G>A	p.Arg1873=	synonymous_variant	40/49	1	NM_000260.4

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2553 AN: 152178 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00476

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0154 AC: 3804 AN: 247660 Hom.: 36 AF XY: 0.0157 AC XY: 2109 AN XY: 134606

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00200

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0220 AC: 32173 AN: 1461172 Hom.: 445 Cov.: 32 AF XY: 0.0217 AC XY: 15761 AN XY: 726870

Gnomad4 AFR exome AF: 0.00344

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00234

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0174

GnomAD4 genome AF: 0.0168 AC: 2552 AN: 152296 Hom.: 33 Cov.: 32 AF XY: 0.0162 AC XY: 1207 AN XY: 74480

Gnomad4 AFR AF: 0.00474

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0205

Gnomad4 NFE AF: 0.0270

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0216 Hom.: 23

Bravo AF: 0.0159

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0253

EpiControl AF: 0.0210

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

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

- -

Usher syndrome type 1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	8.1
Dann	Benign	0.61

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: rs45450893; hg19: chr11-76916645;