rs121912559

Positions:

• chr6-75840678-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PS1_Moderate BP4_Strong BS1_Supporting BS2

The NM_004999.4(MYO6):​c.647A>T​(p.Glu216Val) variant causes a missense change. The variant allele was found at a frequency of 0.000191 in 1,606,212 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5
• Conservation: PhyloP100: 5.96

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 -7 ACMG points.

• PS1: Transcript NM_004999.4 (MYO6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Computational evidence support a benign effect (MetaRNN=0.01628673).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000197 (30/152324) while in subpopulation SAS AF= 0.00601 (29/4826). AF 95% confidence interval is 0.0043. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.647A>T	p.Glu216Val	missense_variant	8/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.647A>T	p.Glu216Val	missense_variant	8/35	1	NM_004999.4	A1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000319 AC: 80 AN: 250648 Hom.: 1 AF XY: 0.000443 AC XY: 60 AN XY: 135558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00259

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000190 AC: 276 AN: 1453888 Hom.: 2 Cov.: 29 AF XY: 0.000264 AC XY: 191 AN XY: 723908

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00306

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000428 AC: 52

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 26, 2022	The p.Glu216Val variant in MYO6 has been reported in homozygous state in one Pakistani individual with severe-to-profound hearing loss and was not identified in 540 ethnically matched chromosomes (Ahmed 2003). Although this information suggests a role for this variant, it is possible that the variant segregates with another variant that is causative for the hearing loss. Additional evidence, such as screening for this variant in a large ethnically-matched control population and functional studies, is needed to assume pathogenicity. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Glu216Val variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 22, 2020	This sequence change replaces glutamic acid with valine at codon 216 of the MYO6 protein (p.Glu216Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is present in population databases (rs121912559, ExAC 0.3%). This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 12687499). ClinVar contains an entry for this variant (Variation ID: 8580). This variant has been reported to affect MYO6 protein function (PMID: 32143290). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2023	Observed in homozygous state in a patient with congenital sensorineural hearing loss in the literature (Ahmed et al., 2003), however, this individual was not screened for variants in other genes associated with hearing loss, and the variant was also observed in at least one homozygous individual in large population cohorts (gnomAD); Published functional studies are inconclusive regarding the functional impact of this variant (Oka et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31250571, 29224747, 30245029, 32143290, 12687499) -

Autosomal recessive nonsyndromic hearing loss 37 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2003	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 27, 2016	The MYO6 c.647A>T (p.Glu216Val) missense variant has been reported in at least one study in a homozygous state in one individual with hearing loss and in a heterozygous state in at least one unaffected family member (Ahmed et al. 2003). The p.Glu216Val variant was absent from 351 controls, but is reported at a frequency of 0.03398 in the Gujarati Indian in Houston, Texas population from the 1000 Genomes Project. This allele frequency is high but is consistent with the disease prevalence. Computational analyses of the p.Glu216Val variant by Butt et al. (2012) showed that the variant may affect protein stability and result in structural abnormalities that could affect binding properties. The evidence for this variant is limited. The p.Glu216Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Autosomal dominant nonsyndromic hearing loss 22 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.;.;T;T
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;D;D;D;D
MetaRNN	Benign	0.016	T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.2	D;D;D;.;D;.
REVEL	Pathogenic	0.73
Sift	Benign	0.12	T;T;T;.;T;.
Sift4G	Benign	0.16	T;T;T;T;T;T
Polyphen		0.11, 0.64	.;B;P;B;.;.
Vest4		0.82
MutPred		0.79		Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);
MVP		0.86
MPC		0.30
ClinPred		0.15	T
GERP RS		5.2
gMVP		0.58

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: rs121912559; hg19: chr6-76550395;