rs111530469

Variant names:

• chr6-75855204-G-A
• rs111530469
• NM_004999.4:c.1144G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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 -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 VariationId is 259604.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	NM_004999.4	MANE Select	c.1144G>A	p.Asp382Asn	missense	Exon 12 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.1144G>A	p.Asp382Asn	missense	Exon 12 of 36	NP_001355794.1
	MYO6	NM_001368866.1		c.1144G>A	p.Asp382Asn	missense	Exon 12 of 35	NP_001355795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	ENST00000369977.8	TSL:1 MANE Select	c.1144G>A	p.Asp382Asn	missense	Exon 12 of 35	ENSP00000358994.3
	MYO6	ENST00000615563.4	TSL:1	c.1144G>A	p.Asp382Asn	missense	Exon 11 of 32	ENSP00000478013.1
	MYO6	ENST00000664640.1		c.1144G>A	p.Asp382Asn	missense	Exon 12 of 36	ENSP00000499278.1

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

GnomAD2 exomes AF: 0.000439 AC: 110 AN: 250850 AF XY: 0.000361

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 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

African (AFR) AF: 0.00445 AC: 149 AN: 33462

American (AMR) AF: 0.000470 AC: 21 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111628

Other (OTH) AF: 0.000464 AC: 28 AN: 60360

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

African (AFR) AF: 0.00465 AC: 193 AN: 41522

American (AMR) AF: 0.000458 AC: 7 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000595 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 22 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 37 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.5	L
PhyloP100		9.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.48
Sift	Benign	0.043	D
Sift4G	Uncertain	0.045	D
Polyphen		0.89	P
Vest4		0.45
MVP		0.84
MPC		0.25
ClinPred		0.034	T
GERP RS		5.3
gMVP		0.29
Mutation Taster		=99/1	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: rs111530469; hg19: chr6-76564921;