rs34477144

Positions:

• chr11-77156699-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000260.4(MYO7A):​c.510G>A​(p.Leu170=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00175 in 1,614,014 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (20 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 4.04

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-77156699-G-A is Benign according to our data. Variant chr11-77156699-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43272.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=2}. Variant chr11-77156699-G-A is described in Lovd as [Benign]. Variant chr11-77156699-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00178 (2599/1461690) while in subpopulation MID AF= 0.0347 (200/5766). AF 95% confidence interval is 0.0308. There are 20 homozygotes in gnomad4_exome. There are 1407 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.510G>A	p.Leu170=	synonymous_variant	6/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.510G>A	p.Leu170=	synonymous_variant	6/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.510G>A	p.Leu170=	synonymous_variant	6/49	1		P1
MYO7A	ENST00000409619.6	c.477G>A	p.Leu159=	synonymous_variant	7/50	1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152206 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00266 AC: 664 AN: 249240 Hom.: 6 AF XY: 0.00292 AC XY: 395 AN XY: 135222

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00395

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00446

GnomAD4 exome AF: 0.00178 AC: 2599 AN: 1461690 Hom.: 20 Cov.: 32 AF XY: 0.00194 AC XY: 1407 AN XY: 727130

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00394

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152324 Hom.: 3 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74484

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00262 Hom.: 1

Bravo AF: 0.00178

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2018	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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MYO7A: BP4, BP7, BS2 -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 17, 2013	Leu170Leu in exon 6 of MYO7A: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.3% (23/8444) of Europ ean American chromosomes in a broad population by the NHLBI Exome sequencing pro ject (http://evs.gs.washington.edu/EVS/; dbSNP rs34477144) and was reported in 2 /664 (0.3%) of control chromosomes (Roux 2006). -

Usher syndrome type 1 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
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 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

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. -

Usher syndrome type 1B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 06, 2019

- -

MYO7A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.5
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34477144; hg19: chr11-76867745;