6-75848543-ATTTTT-ATTTTTT

Variant names:

• chr6-75848543-A-AT
• rs144408691
• NM_004999.4:c.1078+19dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004999.4(MYO6):​c.1078+19dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 1,609,652 control chromosomes in the GnomAD database, including 6,046 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (776 hom., cov: 31)
  • Exomes 𝑓: 0.074 (5270 hom.)
• Consequence: MYO6 NM_004999.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.41
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 6-75848543-A-AT is Benign according to our data. Variant chr6-75848543-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.1078+19dupT		intron_variant	Intron 11 of 34	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.1078+12_1078+13insT		intron_variant	Intron 11 of 34	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes AF: 0.0884 AC: 13425 AN: 151884 Hom.: 778 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0743

Gnomad ASJ AF: 0.0381

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0826

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.0847

GnomAD2 exomes AF: 0.0880 AC: 21733 AN: 246976 AF XY: 0.0864

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.0715

Gnomad ASJ exome AF: 0.0476

Gnomad EAS exome AF: 0.301

Gnomad FIN exome AF: 0.0814

Gnomad NFE exome AF: 0.0578

Gnomad OTH exome AF: 0.0780

GnomAD4 exome AF: 0.0739 AC: 107776 AN: 1457652 Hom.: 5270 Cov.: 31 AF XY: 0.0742 AC XY: 53806 AN XY: 724952

African (AFR) AF: 0.120 AC: 3985 AN: 33192

American (AMR) AF: 0.0702 AC: 3094 AN: 44096

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 1221 AN: 26036

East Asian (EAS) AF: 0.280 AC: 11096 AN: 39614

South Asian (SAS) AF: 0.0991 AC: 8413 AN: 84914

European-Finnish (FIN) AF: 0.0807 AC: 4300 AN: 53290

Middle Eastern (MID) AF: 0.0462 AC: 266 AN: 5760

European-Non Finnish (NFE) AF: 0.0632 AC: 70138 AN: 1110566

Other (OTH) AF: 0.0874 AC: 5263 AN: 60184

GnomAD4 genome AF: 0.0883 AC: 13428 AN: 152000 Hom.: 776 Cov.: 31 AF XY: 0.0894 AC XY: 6641 AN XY: 74320

African (AFR) AF: 0.121 AC: 5023 AN: 41482

American (AMR) AF: 0.0741 AC: 1128 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0381 AC: 132 AN: 3468

East Asian (EAS) AF: 0.294 AC: 1522 AN: 5172

South Asian (SAS) AF: 0.112 AC: 537 AN: 4814

European-Finnish (FIN) AF: 0.0826 AC: 873 AN: 10570

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0590 AC: 4009 AN: 67948

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0295 Hom.: 24

Bravo AF: 0.0907

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nonsyndromic Hearing Loss, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing loss, autosomal recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
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: rs144408691; hg19: chr6-76558260;