rs121912559

Positions:

chr6-75840678-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PS1_ModerateBP4_StrongBS1_SupportingBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 5.96

Variant links:

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]

MYO6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
MYO6	NM_004999.4 linkuse as main transcript	c.647A>T	p.Glu216Val	missense_variant	8/35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8 linkuse as main transcript	c.647A>T	p.Glu216Val	missense_variant	8/35	1	NM_004999.4	ENSP00000358994	A1	Q9UM54-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

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:

AN:

250648

Hom.:

AF XY:

0.000443

AC XY:

AN XY:

135558

show subpopulations

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.:

Cov.:

AF XY:

0.000264

AC XY:

191

AN XY:

723908

show subpopulations

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:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74494

show subpopulations

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.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000428

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	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	Aug 05, 2024	Observed in homozygous state in a patient with congenital sensorineural hearing loss in the literature, however, this individual was not screened for variants in other genes associated with hearing loss (PMID: 12687499), and this variant was observed as homozygous in at least one individual in the general population (gnomAD); Published functional studies are inconclusive regarding the functional impact of this variant (PMID: 32143290); 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, 39019031, 12687499) -

Autosomal recessive nonsyndromic hearing loss 37

Pathogenic:1Uncertain: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

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

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

LIST_S2

Uncertain

0.88

D;.;D;D;D;D

MetaRNN

Benign

0.016

T;T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.3

.;L;L;L;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.76

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over