rs41269323

Positions:

chr6-75914821-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000369977.8(MYO6):c.3667G>A(p.Asp1223Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00954 in 1,614,072 control chromosomes in the GnomAD database, including 114 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 0.0080 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 98 hom. )

Consequence

MYO6
ENST00000369977.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 9.57

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010249913).

BP6

Variant 6-75914821-G-A is Benign according to our data. Variant chr6-75914821-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45159.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}. Variant chr6-75914821-G-A is described in Lovd as [Benign]. Variant chr6-75914821-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00803 (1223/152302) while in subpopulation NFE AF= 0.0102 (693/68024). AF 95% confidence interval is 0.00956. There are 16 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4 linkuse as main transcript	c.3667G>A	p.Asp1223Asn	missense_variant	35/35	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.3667G>A	p.Asp1223Asn	missense_variant	35/35	1	NM_004999.4	ENSP00000358994	A1	Q9UM54-1

Frequencies

GnomAD3 genomes

AF:

0.00804

AC:

1224

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.0441

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.0104

AC:

2622

AN:

251390

Hom.:

AF XY:

0.0110

AC XY:

1494

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00639

Gnomad ASJ exome

AF:

0.0449

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00725

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00970

AC:

14175

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00972

AC XY:

7066

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00125

Gnomad4 AMR exome

AF:

0.00662

Gnomad4 ASJ exome

AF:

0.0435

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00710

Gnomad4 FIN exome

AF:

0.0103

Gnomad4 NFE exome

AF:

0.00961

Gnomad4 OTH exome

AF:

0.0121

GnomAD4 genome

AF:

0.00803

AC:

1223

AN:

152302

Hom.:

Cov.:

AF XY:

0.00819

AC XY:

610

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.0441

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00830

Gnomad4 FIN

AF:

0.0136

Gnomad4 NFE

AF:

0.0102

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.00746

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0130

AC:

112

ExAC

AF:

0.00995

AC:

1208

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.0140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2011	Asp1223Asn in exon 35 of MYO6: This variant is not expected to have clinical sig nificance because it was identified in 0.8% (44/5483 chromosomes) of a broad pop ulation (dbSNP rs41269323) and computational analyses do not predict a high like lihood of impact to the protein. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2018	This variant is associated with the following publications: (PMID: 29224747) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MYO6: PP3, BS1, BS2 -

Autosomal recessive nonsyndromic hearing loss 37

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 22

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;.;.;T;T

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;.;D;D;D;D

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Pathogenic

0.84

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.5

.;D;D;.;D;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.0020

.;D;D;.;T;.

Sift4G

Benign

0.062

T;T;T;T;T;T

Polyphen

1.0

.;D;D;D;.;.

Vest4

0.60

MPC

0.91

ClinPred

0.023

GERP RS

6.1

gMVP

0.82

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