rs55905349

chr6-75892565-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004999.4(MYO6):c.2982G>A(p.Glu994=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00667 in 1,613,928 control chromosomes in the GnomAD database, including 55 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 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (50 hom.)
• Consequence: MYO6 NM_004999.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.35

Genes affected

MYO6 (HGNC:7605): (myosin VI) This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 6-75892565-G-A is Benign according to our data. Variant chr6-75892565-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45151.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=2, Uncertain_significance=1}. Variant chr6-75892565-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00482 (734/152304) while in subpopulation NFE AF= 0.00801 (545/68000). AF 95% confidence interval is 0.00746. There are 5 homozygotes in gnomad4. There are 334 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.2982G>A	p.Glu994=	synonymous_variant	28/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.2982G>A	p.Glu994=	synonymous_variant	28/35	1	NM_004999.4	A1

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 736 AN: 152186 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00803

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00526 AC: 1323 AN: 251464 Hom.: 2 AF XY: 0.00542 AC XY: 737 AN XY: 135908

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00531

Gnomad NFE exome AF: 0.00816

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00686 AC: 10034 AN: 1461624 Hom.: 50 Cov.: 31 AF XY: 0.00676 AC XY: 4912 AN XY: 727122

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00543

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00186

Gnomad4 FIN exome AF: 0.00588

Gnomad4 NFE exome AF: 0.00789

Gnomad4 OTH exome AF: 0.00595

GnomAD4 genome AF: 0.00482 AC: 734 AN: 152304 Hom.: 5 Cov.: 32 AF XY: 0.00448 AC XY: 334 AN XY: 74480

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.00801

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00708 Hom.: 2

Bravo AF: 0.00463

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYO6: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2019	This variant is associated with the following publications: (PMID: 11167014) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

not specified Benign:3

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 16, 2012	Glu994Glu in exon 28 of MYO6: 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, has been identified in 0.8% (57/7020) of European American chromosomes and 0.16% (6/3738) of African American chromosomes in a br oad population by the NHLBI Exome sequencing project (http://evs.gs.washington.e du/EVS/ ; dbSNP rs55905349) and is reported as benign in one publication (Ahituv 2000). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2016	- -

Autosomal recessive nonsyndromic hearing loss 37 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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal dominant nonsyndromic hearing loss 22 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	1.9
Dann	Benign	0.39
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.9

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: rs55905349; hg19: chr6-76602282;