chr6-75914821-G-A

Variant names:

• chr6-75914821-G-A
• rs41269323
• NM_004999.4:c.3667G>A

Variant summary

Our verdict is Benign. The variant received -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). The gene MYO6 is included in the ClinGen Criteria Specification Registry.

• 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
• Publications: 23 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, ClinGen
• autosomal recessive nonsyndromic hearing loss 37

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: 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

Specifications for MYO6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -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 VariationId is 45159.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	NM_004999.4	MANE Select	c.3667G>A	p.Asp1223Asn	missense	Exon 35 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.3694G>A	p.Asp1232Asn	missense	Exon 36 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.3667G>A	p.Asp1223Asn	missense	Exon 35 of 35	NP_001355795.1	A0A1Y0BRN3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	ENST00000369977.8	TSL:1 MANE Select	c.3667G>A	p.Asp1223Asn	missense	Exon 35 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.3598G>A	p.Asp1200Asn	missense	Exon 32 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.3694G>A	p.Asp1232Asn	missense	Exon 36 of 36	ENSP00000499278.1	A0A590UJ40

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

GnomAD2 exomes AF: 0.0104 AC: 2622 AN: 251390 AF XY: 0.0110

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 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

African (AFR) AF: 0.00125 AC: 42 AN: 33472

American (AMR) AF: 0.00662 AC: 296 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 1136 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00710 AC: 612 AN: 86244

European-Finnish (FIN) AF: 0.0103 AC: 549 AN: 53418

Middle Eastern (MID) AF: 0.0220 AC: 127 AN: 5766

European-Non Finnish (NFE) AF: 0.00961 AC: 10683 AN: 1111924

Other (OTH) AF: 0.0121 AC: 728 AN: 60390

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

African (AFR) AF: 0.00166 AC: 69 AN: 41570

American (AMR) AF: 0.00562 AC: 86 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00830 AC: 40 AN: 4822

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 693 AN: 68024

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.0102 Hom.: 40

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 22 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.010	T
MetaSVM	Pathogenic	0.84	D
PhyloP100		9.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.062	T
Polyphen		1.0	D
Vest4		0.60
MPC		0.91
ClinPred		0.023	T
GERP RS		6.1
gMVP		0.82
Mutation Taster		=12/88	disease causing

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: rs41269323; hg19: chr6-76624538;