rs876657710

Variant names:

• chr6-75832908-C-G
• rs876657710
• NM_004999.4:c.458C>G
• MYO6 p.Ser153*

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 PM2 PP5_Moderate

The NM_004999.4(MYO6):​c.458C>G​(p.Ser153*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000271418: "In vitro studies support a causal role for MYO6 variants in hearing loss (Avraham, 1995, Kiernan 1999, Williams 2013)."". Variant results in nonsense mediated mRNA decay. The gene MYO6 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO6 NM_004999.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.50
• Publications: 1 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000271418: "In vitro studies support a causal role for MYO6 variants in hearing loss (Avraham, 1995, Kiernan 1999, Williams 2013)."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-75832908-C-G is Pathogenic according to our data. Variant chr6-75832908-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 228376.Status of the report is criteria_provided_single_submitter, 1 stars.

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.458C>G	p.Ser153*	stop_gained	Exon 6 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.458C>G	p.Ser153*	stop_gained	Exon 6 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.458C>G	p.Ser153*	stop_gained	Exon 6 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.458C>G	p.Ser153*	stop_gained	Exon 6 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.458C>G	p.Ser153*	stop_gained	Exon 5 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.458C>G	p.Ser153*	stop_gained	Exon 6 of 36	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.5
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs876657710;

hg19: chr6-76542625;