rs1280046

Variant names:

• chr6-75817326-G-A
• rs1280046
• NM_004999.4:c.-47-175G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004999.4(MYO6):​c.-47-175G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00803 in 148,380 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0080 (7 hom., cov: 32)
• Consequence: MYO6 NM_004999.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.18
• 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: 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=-0.9).
• BP6: Variant 6-75817326-G-A is Benign according to our data. Variant chr6-75817326-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1216398.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00803 (1191/148380) while in subpopulation NFE AF = 0.0138 (934/67604). AF 95% confidence interval is 0.0131. There are 7 homozygotes in GnomAd4. There are 557 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.-47-175G>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.-47-175G>A		intron_variant	Intron 1 of 34	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 1191 AN: 148320 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.0341

Gnomad AMR AF: 0.00580

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00466

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.00537

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

GnomAD4 genome AF: 0.00803 AC: 1191 AN: 148380 Hom.: 7 Cov.: 32 AF XY: 0.00769 AC XY: 557 AN XY: 72404

African (AFR) AF: 0.00202 AC: 80 AN: 39582

American (AMR) AF: 0.00580 AC: 87 AN: 15010

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 4874

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4740

European-Finnish (FIN) AF: 0.00466 AC: 46 AN: 9866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0138 AC: 934 AN: 67604

Other (OTH) AF: 0.00531 AC: 11 AN: 2070

Alfa AF: 0.0109 Hom.: 3

Bravo AF: 0.00790

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 22, 2018

GeneDx

Significance: Likely 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	-0.90
CADD	Benign	3.6
DANN	Benign	0.27
PhyloP100		1.2
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	polymorphism

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: rs1280046; hg19: chr6-76527043;