rs3798425

Variant names:

• chr6-75897833-C-G
• rs3798425
• NM_004999.4:c.3138-540C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004999.4(MYO6):​c.3138-540C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,130 control chromosomes in the GnomAD database, including 5,575 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (5575 hom., cov: 33)
• Consequence: MYO6 NM_004999.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.753
• Publications: 5 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: PanelApp Australia, 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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.334 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.3138-540C>G		intron	N/A	NP_004990.3
	MYO6	NM_001368865.1		c.3165-540C>G		intron	N/A	NP_001355794.1
	MYO6	NM_001368866.1		c.3165-540C>G		intron	N/A	NP_001355795.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	ENST00000369977.8	TSL:1 MANE Select	c.3138-540C>G		intron	N/A	ENSP00000358994.3
	MYO6	ENST00000615563.4	TSL:1	c.3107+5143C>G		intron	N/A	ENSP00000478013.1
	MYO6	ENST00000664640.1		c.3165-540C>G		intron	N/A	ENSP00000499278.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36752 AN: 152012 Hom.: 5576 Cov.: 33

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.241

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

GnomAD4 genome AF: 0.241 AC: 36739 AN: 152130 Hom.: 5575 Cov.: 33 AF XY: 0.241 AC XY: 17897 AN XY: 74350

African (AFR) AF: 0.0627 AC: 2605 AN: 41530

American (AMR) AF: 0.218 AC: 3335 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1109 AN: 3468

East Asian (EAS) AF: 0.198 AC: 1029 AN: 5184

South Asian (SAS) AF: 0.281 AC: 1354 AN: 4826

European-Finnish (FIN) AF: 0.324 AC: 3424 AN: 10556

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22982 AN: 67972

Other (OTH) AF: 0.237 AC: 500 AN: 2108

Alfa AF: 0.276 Hom.: 823

Bravo AF: 0.224

Asia WGS AF: 0.215 AC: 751 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.67
PhyloP100		0.75
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

Other links and lift over

dbSNP: rs3798425; hg19: chr6-76607550;