rs138200430

Positions:

• chr6-75861098-ATG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004999.4(MYO6):​c.1546+7_1546+8del variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,604,278 control chromosomes in the GnomAD database, including 746 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (72 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (674 hom.)
• Consequence: MYO6 NM_004999.4 splice_donor_5th_base, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.38

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 -16 ACMG points.

• BP6: Variant 6-75861098-ATG-A is Benign according to our data. Variant chr6-75861098-ATG-A is described in ClinVar as [Likely_benign]. Clinvar id is 45137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4	c.1546+7_1546+8del		splice_donor_5th_base_variant, intron_variant		ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.1546+7_1546+8del		splice_donor_5th_base_variant, intron_variant		1	NM_004999.4	ENSP00000358994	A1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1987 AN: 152162 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0256 AC: 6432 AN: 251104 Hom.: 313 AF XY: 0.0244 AC XY: 3317 AN XY: 135750

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.0190

Gnomad FIN exome AF: 0.0648

Gnomad NFE exome AF: 0.00292

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.00981 AC: 14251 AN: 1451998 Hom.: 674 AF XY: 0.00991 AC XY: 7161 AN XY: 722942

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0298

Gnomad4 ASJ exome AF: 0.00649

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.0175

Gnomad4 FIN exome AF: 0.0609

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0131 AC: 1988 AN: 152280 Hom.: 72 Cov.: 32 AF XY: 0.0165 AC XY: 1230 AN XY: 74454

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.0695

Gnomad4 NFE AF: 0.00200

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00702 Hom.: 5

Bravo AF: 0.0100

Asia WGS AF: 0.0720 AC: 247 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 14, 2012

1546+7_1546+8del in intron 15 of MYO6: This variant is not expected to have clin ical significance because it has been identified in 16% (93/572) of Asian chromo somes by 1000 Genomes Project (dbSNP rs138200430). -

Nonsyndromic Hearing Loss, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hearing loss, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs3831003; hg19: chr6-76570815;