rs1341567

chr6-75918459-A-Cchr6-75918459-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004999.4(MYO6):c.*3447A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,200 control chromosomes in the GnomAD database, including 7,878 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (7878 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: MYO6 NM_004999.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.391

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-75918459-A-C is Benign according to our data. Variant chr6-75918459-A-C is described in ClinVar as [Benign]. Clinvar id is 358042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75918459-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.*3447A>C		3_prime_UTR_variant	35/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.*3447A>C		3_prime_UTR_variant	35/35	1	NM_004999.4	A1
MYO6	ENST00000369985.9	c.*3447A>C		3_prime_UTR_variant	33/33	5		A1
MYO6	ENST00000664640.1	c.*3447A>C		3_prime_UTR_variant	36/36			A1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27157 AN: 152082 Hom.: 7864 Cov.: 32

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0795

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.133

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.179 AC: 27220 AN: 152200 Hom.: 7878 Cov.: 32 AF XY: 0.173 AC XY: 12838 AN XY: 74416

Gnomad4 AFR AF: 0.608

Gnomad4 AMR AF: 0.0794

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0245

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00541

Gnomad4 OTH AF: 0.132

Alfa AF: 0.0132 Hom.: 468

Bravo AF: 0.204

Asia WGS AF: 0.0530 AC: 186 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Autosomal recessive nonsyndromic hearing loss 37 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.8
Dann	Benign	0.67

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1341567; hg19: chr6-76628176;