rs41269323

chr6-75914821-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004999.4(MYO6):c.3667G>A(p.Asp1223Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00954 in 1,614,072 control chromosomes in the GnomAD database, including 114 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 0.0080 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (98 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 9.57

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010249913).
• BP6: Variant 6-75914821-G-A is Benign according to our data. Variant chr6-75914821-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45159.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}. Variant chr6-75914821-G-A is described in Lovd as [Benign]. Variant chr6-75914821-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00803 (1223/152302) while in subpopulation NFE AF= 0.0102 (693/68024). AF 95% confidence interval is 0.00956. There are 16 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.3667G>A	p.Asp1223Asn	missense_variant	35/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.3667G>A	p.Asp1223Asn	missense_variant	35/35	1	NM_004999.4	A1

Frequencies

GnomAD3 genomes AF: 0.00804 AC: 1224 AN: 152184 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.0104 AC: 2622 AN: 251390 Hom.: 31 AF XY: 0.0110 AC XY: 1494 AN XY: 135868

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.0449

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00725

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00970 AC: 14175 AN: 1461770 Hom.: 98 Cov.: 31 AF XY: 0.00972 AC XY: 7066 AN XY: 727196

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00662

Gnomad4 ASJ exome AF: 0.0435

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00710

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.00961

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00803 AC: 1223 AN: 152302 Hom.: 16 Cov.: 32 AF XY: 0.00819 AC XY: 610 AN XY: 74468

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.0441

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0110 Hom.: 18

Bravo AF: 0.00746

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.00995 AC: 1208

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0124

EpiControl AF: 0.0140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2011	Asp1223Asn in exon 35 of MYO6: This variant is not expected to have clinical sig nificance because it was identified in 0.8% (44/5483 chromosomes) of a broad pop ulation (dbSNP rs41269323) and computational analyses do not predict a high like lihood of impact to the protein. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2018	This variant is associated with the following publications: (PMID: 29224747) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MYO6: PP3, BS1, BS2 -

Autosomal recessive nonsyndromic hearing loss 37 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Autosomal dominant nonsyndromic hearing loss 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.;.;T;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Pathogenic	0.84	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
REVEL	Uncertain	0.61
Sift4G	Benign	0.062	T;T;T;T;T;T
Polyphen		1.0	.;D;D;D;.;.
Vest4		0.60
MPC		0.91
ClinPred		0.023	T
GERP RS		6.1
gMVP		0.82

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: rs41269323; hg19: chr6-76624538;