NM_004999.4:c.-47-197C>A

Variant names:

• chr6-75817304-C-A
• rs890890661
• NM_004999.4:c.-47-197C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004999.4(MYO6):​c.-47-197C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). The gene MYO6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.029 (0 hom., cov: 12)
  • Failed GnomAD Quality Control
• Consequence: MYO6 NM_004999.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.695
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-75817304-C-A is Benign according to our data. Variant chr6-75817304-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1195543.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.-47-197C>A		intron	N/A	NP_004990.3
	MYO6	NM_001368865.1		c.-47-197C>A		intron	N/A	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.-47-197C>A		intron	N/A	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.-47-197C>A		intron	N/A	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000664640.1		c.-47-197C>A		intron	N/A	ENSP00000499278.1	A0A590UJ40
	MYO6	ENST00000947981.1		c.-47-197C>A		intron	N/A	ENSP00000618040.1

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 1793 AN: 61246 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.0803

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0359

Gnomad EAS AF: 0.00880

Gnomad SAS AF: 0.0198

Gnomad FIN AF: 0.0336

Gnomad MID AF: 0.0676

Gnomad NFE AF: 0.0367

Gnomad OTH AF: 0.0303

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0293 AC: 1798 AN: 61262 Hom.: 0 Cov.: 12 AF XY: 0.0293 AC XY: 848 AN XY: 28932

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0194 AC: 368 AN: 18940

American (AMR) AF: 0.0341 AC: 175 AN: 5134

Ashkenazi Jewish (ASJ) AF: 0.0359 AC: 52 AN: 1450

East Asian (EAS) AF: 0.00884 AC: 24 AN: 2716

South Asian (SAS) AF: 0.0203 AC: 43 AN: 2114

European-Finnish (FIN) AF: 0.0336 AC: 91 AN: 2706

Middle Eastern (MID) AF: 0.0714 AC: 5 AN: 70

European-Non Finnish (NFE) AF: 0.0367 AC: 993 AN: 27022

Other (OTH) AF: 0.0299 AC: 25 AN: 836

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.59
PhyloP100		0.69
PromoterAI		-0.0078	Neutral

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: rs890890661; hg19: chr6-76527021;