rs3831003

Variant names:

• chr6-75861098-ATG-A
• rs3831003
• NM_004999.4:c.1546+7_1546+8delGT

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.1546+7_1546+8delGT variant causes a splice region, 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_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.38
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: 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 6-75861098-ATG-A is Benign according to our data. Variant chr6-75861098-ATG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	NM_004999.4	MANE Select	c.1546+7_1546+8delGT		splice_region intron	N/A	NP_004990.3
	MYO6	NM_001368865.1		c.1546+7_1546+8delGT		splice_region intron	N/A	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.1546+7_1546+8delGT		splice_region intron	N/A	NP_001355795.1	A0A1Y0BRN3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	ENST00000369977.8	TSL:1 MANE Select	c.1546+4_1546+5delTG		splice_region intron	N/A	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.1546+4_1546+5delTG		splice_region intron	N/A	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.1546+4_1546+5delTG		splice_region intron	N/A	ENSP00000499278.1	A0A590UJ40

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

GnomAD2 exomes AF: 0.0256 AC: 6432 AN: 251104 AF XY: 0.0244

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 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

African (AFR) AF: 0.000180 AC: 6 AN: 33280

American (AMR) AF: 0.0298 AC: 1331 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00649 AC: 169 AN: 26058

East Asian (EAS) AF: 0.152 AC: 5984 AN: 39438

South Asian (SAS) AF: 0.0175 AC: 1506 AN: 86018

European-Finnish (FIN) AF: 0.0609 AC: 3237 AN: 53186

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5746

European-Non Finnish (NFE) AF: 0.00108 AC: 1197 AN: 1103534

Other (OTH) AF: 0.0135 AC: 811 AN: 60060

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

African (AFR) AF: 0.000337 AC: 14 AN: 41584

American (AMR) AF: 0.0130 AC: 199 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.146 AC: 754 AN: 5180

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4824

European-Finnish (FIN) AF: 0.0695 AC: 736 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00200 AC: 136 AN: 68026

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00702 Hom.: 5

Bravo AF: 0.0100

Asia WGS AF: 0.0720 AC: 247 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 37;C2931767:Autosomal dominant nonsyndromic hearing loss 22 (1)
-	-	1	Hearing loss, autosomal recessive (1)
-	-	1	Nonsyndromic Hearing Loss, Dominant (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=99/1	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: rs3831003; hg19: chr6-76570815; COSMIC: COSV107477131; COSMIC: COSV107477131;