rs111530469

Positions:

• chr6-75855204-G-A
• chr6-75855204-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_004999.4(MYO6):​c.1144G>A​(p.Asp382Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,613,482 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 9.52

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0103028715).
• BP6: Variant 6-75855204-G-A is Benign according to our data. Variant chr6-75855204-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259604.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00135 (206/152224) while in subpopulation AFR AF= 0.00465 (193/41522). AF 95% confidence interval is 0.00411. There are 1 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.1144G>A	p.Asp382Asn	missense_variant	12/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.1144G>A	p.Asp382Asn	missense_variant	12/35	1	NM_004999.4	A1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152106 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00452

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000439 AC: 110 AN: 250850 Hom.: 1 AF XY: 0.000361 AC XY: 49 AN XY: 135566

Gnomad AFR exome AF: 0.00542

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1461258 Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 111 AN XY: 726918

Gnomad4 AFR exome AF: 0.00445

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152224 Hom.: 1 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74416

Gnomad4 AFR AF: 0.00465

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000333 Hom.: 0

Bravo AF: 0.00161

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000577 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -

Autosomal recessive nonsyndromic hearing loss 37 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal dominant nonsyndromic hearing loss 22 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;.;.;.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.5	.;L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D;D;D;.;D;.
REVEL	Uncertain	0.48
Sift	Benign	0.043	D;D;D;.;D;.
Sift4G	Uncertain	0.045	D;D;D;D;D;D
Polyphen		0.89, 0.16	.;P;B;P;.;.
Vest4		0.45
MVP		0.84
MPC		0.25
ClinPred		0.034	T
GERP RS		5.3
gMVP		0.29

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: rs111530469; hg19: chr6-76564921;