rs1045758

Variant names:

• chr6-75915471-A-G
• rs1045758
• NM_004999.4:c.*459A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004999.4(MYO6):​c.*459A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 169,082 control chromosomes in the GnomAD database, including 1,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene MYO6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.13 (1362 hom., cov: 33)
  • Exomes 𝑓: 0.12 (146 hom.)
• Consequence: MYO6 NM_004999.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00900
• Publications: 7 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)
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-75915471-A-G is Benign according to our data. Variant chr6-75915471-A-G is described in ClinVar as Benign. ClinVar VariationId is 358005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

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.*459A>G		3_prime_UTR	Exon 35 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.*459A>G		3_prime_UTR	Exon 36 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.*459A>G		3_prime_UTR	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.*459A>G		3_prime_UTR	Exon 35 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000664640.1		c.*459A>G		3_prime_UTR	Exon 36 of 36	ENSP00000499278.1	A0A590UJ40
	MYO6	ENST00000947981.1		c.*459A>G		3_prime_UTR	Exon 36 of 36	ENSP00000618040.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19751 AN: 152112 Hom.: 1362 Cov.: 33

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0371

Gnomad SAS AF: 0.0901

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.123 AC: 2070 AN: 16852 Hom.: 146 Cov.: 0 AF XY: 0.123 AC XY: 1070 AN XY: 8724

African (AFR) AF: 0.117 AC: 30 AN: 256

American (AMR) AF: 0.0995 AC: 260 AN: 2614

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 26 AN: 258

East Asian (EAS) AF: 0.0206 AC: 21 AN: 1018

South Asian (SAS) AF: 0.0959 AC: 222 AN: 2316

European-Finnish (FIN) AF: 0.133 AC: 65 AN: 488

Middle Eastern (MID) AF: 0.146 AC: 7 AN: 48

European-Non Finnish (NFE) AF: 0.145 AC: 1322 AN: 9088

Other (OTH) AF: 0.153 AC: 117 AN: 766

GnomAD4 genome AF: 0.130 AC: 19751 AN: 152230 Hom.: 1362 Cov.: 33 AF XY: 0.128 AC XY: 9493 AN XY: 74428

African (AFR) AF: 0.115 AC: 4764 AN: 41560

American (AMR) AF: 0.132 AC: 2025 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 376 AN: 3470

East Asian (EAS) AF: 0.0372 AC: 193 AN: 5188

South Asian (SAS) AF: 0.0895 AC: 431 AN: 4814

European-Finnish (FIN) AF: 0.130 AC: 1380 AN: 10590

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10138 AN: 67998

Other (OTH) AF: 0.143 AC: 302 AN: 2112

Alfa AF: 0.137 Hom.: 549

Bravo AF: 0.128

Asia WGS AF: 0.0680 AC: 237 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.73
DANN	Benign	0.69
PhyloP100		-0.0090
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1045758;

hg19: chr6-76625188;