6-75817335-G-A

Variant names:

• chr6-75817335-G-A
• rs56338010
• NM_004999.4:c.-47-166G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004999.4(MYO6):​c.-47-166G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 151,700 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.043 (243 hom., cov: 32)
• Consequence: MYO6 NM_004999.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.27
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 22

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, G2P
• autosomal recessive nonsyndromic hearing loss 37

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-75817335-G-A is Benign according to our data. Variant chr6-75817335-G-A is described in ClinVar as [Benign]. Clinvar id is 1296428.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.-47-166G>A		intron_variant	Intron 1 of 34	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.-47-166G>A		intron_variant	Intron 1 of 34	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6552 AN: 151602 Hom.: 244 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0475

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0713

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0433

Gnomad OTH AF: 0.0491

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0431 AC: 6541 AN: 151700 Hom.: 243 Cov.: 32 AF XY: 0.0456 AC XY: 3381 AN XY: 74106

African (AFR) AF: 0.0106 AC: 440 AN: 41338

American (AMR) AF: 0.0474 AC: 722 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3468

East Asian (EAS) AF: 0.182 AC: 936 AN: 5150

South Asian (SAS) AF: 0.105 AC: 506 AN: 4810

European-Finnish (FIN) AF: 0.0713 AC: 745 AN: 10448

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0433 AC: 2942 AN: 67946

Other (OTH) AF: 0.0487 AC: 102 AN: 2096

Alfa AF: 0.0383 Hom.: 12

Bravo AF: 0.0407

Asia WGS AF: 0.105 AC: 363 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.30
DANN	Benign	0.65
PhyloP100		-1.3
PromoterAI		0.019	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56338010; hg19: chr6-76527052;