rs61732664

Positions:

• chr6-75855180-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000369977.8(MYO6):​c.1120T>C​(p.Tyr374His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,612,678 control chromosomes in the GnomAD database, including 363 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (321 hom.)
• Consequence: MYO6 ENST00000369977.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.50

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020512044).
• BP6: Variant 6-75855180-T-C is Benign according to our data. Variant chr6-75855180-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 45133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4	c.1120T>C	p.Tyr374His	missense_variant	12/35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.1120T>C	p.Tyr374His	missense_variant	12/35	1	NM_004999.4	ENSP00000358994	A1

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1148 AN: 152190 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0621

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00538

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.0172 AC: 4306 AN: 250720 Hom.: 277 AF XY: 0.0130 AC XY: 1766 AN XY: 135522

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00567

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.00377 AC: 5502 AN: 1460370 Hom.: 321 Cov.: 31 AF XY: 0.00320 AC XY: 2327 AN XY: 726536

Gnomad4 AFR exome AF: 0.00168

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00527

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000693

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome AF: 0.00760 AC: 1157 AN: 152308 Hom.: 42 Cov.: 32 AF XY: 0.00827 AC XY: 616 AN XY: 74482

Gnomad4 AFR AF: 0.00332

Gnomad4 AMR AF: 0.0626

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00539

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00121 Hom.: 10

Bravo AF: 0.0130

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0128 AC: 1557

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Nov 01, 2011	Tyr374His in exon 12 of MYO6: This variant is not expected to have clinical sign ificance because this residue is not highly conserved across species. In additio n, this variant has now been identified in 5/29 (17%) Hispanic probands tested b y our laboratory and is listed in dbSNP with a frequency of 0.2% (12/5596) in co ntrol chromosomes (rs61732664). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2014	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 05, 2018	- -

Autosomal recessive nonsyndromic hearing loss 37 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign 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. -

Autosomal recessive nonsyndromic hearing loss 37;C2931767:Autosomal dominant nonsyndromic hearing loss 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.42	T;.;.;.;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.83	T;.;T;T;T;T
MetaRNN	Benign	0.0021	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.045	.;N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;N;N;.;N;.
REVEL	Benign	0.28
Sift	Benign	0.53	T;T;T;.;T;.
Sift4G	Benign	0.54	T;T;T;T;T;T
Polyphen		0.0020, 0.0	.;B;B;B;.;.
Vest4		0.034
MPC		0.34
ClinPred		0.0075	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61732664; hg19: chr6-76564897;