chr6-75914978-A-G

Position:

chr6-75914978-A-G

Variant summary

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

The NM_004999.4(MYO6):c.3824A>G(p.Tyr1275Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00209 in 1,613,628 control chromosomes in the GnomAD database, including 46 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 0.0035 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 40 hom. )

Consequence

MYO6
NM_004999.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 7.11

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:

MYO6 (HGNC:):

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=0.009372115).

BP6

Variant 6-75914978-A-G is Benign according to our data. Variant chr6-75914978-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45160.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=5}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00347 (529/152286) while in subpopulation AMR AF= 0.0102 (156/15294). AF 95% confidence interval is 0.00889. There are 6 homozygotes in gnomad4. There are 351 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4 linkuse as main transcript	c.3824A>G	p.Tyr1275Cys	missense_variant	35/35	ENST00000369977.8	NP_004990.3	Q9UM54-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8 linkuse as main transcript	c.3824A>G	p.Tyr1275Cys	missense_variant	35/35	1	NM_004999.4	ENSP00000358994.3		Q9UM54-1

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

527

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0272

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00636

AC:

1593

AN:

250560

Hom.:

AF XY:

0.00522

AC XY:

707

AN XY:

135476

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0267

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00332

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.000706

Gnomad OTH exome

AF:

0.00508

GnomAD4 exome

AF:

0.00195

AC:

2844

AN:

1461342

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

1268

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0241

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00275

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0236

Gnomad4 NFE exome

AF:

0.000245

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00347

AC:

529

AN:

152286

Hom.:

Cov.:

AF XY:

0.00471

AC XY:

351

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.0102

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00367

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0272

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000591

Hom.:

Bravo

AF:

0.00235

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00520

AC:

631

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 21, 2015	Tyr1275Cys in Exon 35 of MYO6: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (622/116228) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP db SNP rs146461956). -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2018	- -

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. -

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_addAF

Benign

-0.049

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;.;.;.;T;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;.;D;D;D;D

MetaRNN

Benign

0.0094

T;T;T;T;T;T

MetaSVM

Uncertain

0.72

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.1

.;N;N;.;N;.

REVEL

Pathogenic

0.65

Sift

Uncertain

0.019

.;D;D;.;D;.

Sift4G

Uncertain

0.016

D;D;D;D;D;D

Polyphen

1.0

.;D;D;D;.;.

Vest4

0.64

MVP

0.97

MPC

1.0

ClinPred

0.020

GERP RS

6.1

gMVP

0.77

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