rs60970824

chr6-75886971-G-Achr6-75886971-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_004999.4(MYO6):c.2635G>A(p.Asp879Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,613,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.59

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010229707).
• BP6: Variant 6-75886971-G-A is Benign according to our data. Variant chr6-75886971-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00168 (255/152236) while in subpopulation AFR AF= 0.00597 (248/41536). AF 95% confidence interval is 0.00536. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.2635G>A	p.Asp879Asn	missense_variant	25/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.2635G>A	p.Asp879Asn	missense_variant	25/35	1	NM_004999.4	A1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000378 AC: 95 AN: 251146 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135786

Gnomad AFR exome AF: 0.00524

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1461396 Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 101 AN XY: 727020

Gnomad4 AFR exome AF: 0.00616

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.00168 AC: 255 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74438

Gnomad4 AFR AF: 0.00597

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.00147

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 21, 2015	p.Asp879Asn in Exon 25 of MYO6: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (61/10288) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs60970824). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2016	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N;N;N;.;N;.
REVEL	Benign	0.21
Sift	Benign	0.16	T;T;T;.;T;.
Sift4G	Benign	0.20	T;T;T;T;T;T
Polyphen		0.97, 1.0	.;D;D;D;.;.
Vest4		0.53
MVP		0.92
MPC		0.25
ClinPred		0.047	T
GERP RS		5.6
gMVP		0.51

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: rs60970824; hg19: chr6-76596688;