NM_004999.4:c.*350T>C

Variant names:

• chr6-75915362-T-C
• rs699186
• NM_004999.4:c.*350T>C

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.*350T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 338,144 control chromosomes in the GnomAD database, including 24,140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9713 hom., cov: 32)
  • Exomes 𝑓: 0.39 (14427 hom.)
• Consequence: MYO6 NM_004999.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.434
• Publications: 8 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), PanelApp Australia
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-75915362-T-C is Benign according to our data. Variant chr6-75915362-T-C is described in ClinVar as Benign. ClinVar VariationId is 358003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.472 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	NM_004999.4	MANE Select	c.*350T>C		3_prime_UTR	Exon 35 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.*350T>C		3_prime_UTR	Exon 36 of 36	NP_001355794.1
	MYO6	NM_001368866.1		c.*350T>C		3_prime_UTR	Exon 35 of 35	NP_001355795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO6	ENST00000369977.8	TSL:1 MANE Select	c.*350T>C		3_prime_UTR	Exon 35 of 35	ENSP00000358994.3
	MYO6	ENST00000664640.1		c.*350T>C		3_prime_UTR	Exon 36 of 36	ENSP00000499278.1
	MYO6	ENST00000947981.1		c.*350T>C		3_prime_UTR	Exon 36 of 36	ENSP00000618040.1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51693 AN: 151938 Hom.: 9686 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.372

GnomAD4 exome AF: 0.385 AC: 71658 AN: 186088 Hom.: 14427 Cov.: 0 AF XY: 0.382 AC XY: 38372 AN XY: 100352

African (AFR) AF: 0.175 AC: 974 AN: 5556

American (AMR) AF: 0.558 AC: 4416 AN: 7912

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 2140 AN: 4708

East Asian (EAS) AF: 0.393 AC: 3209 AN: 8164

South Asian (SAS) AF: 0.374 AC: 12623 AN: 33728

European-Finnish (FIN) AF: 0.396 AC: 3463 AN: 8750

Middle Eastern (MID) AF: 0.359 AC: 236 AN: 658

European-Non Finnish (NFE) AF: 0.383 AC: 41027 AN: 107142

Other (OTH) AF: 0.377 AC: 3570 AN: 9470

GnomAD4 genome AF: 0.340 AC: 51736 AN: 152056 Hom.: 9713 Cov.: 32 AF XY: 0.344 AC XY: 25554 AN XY: 74312

African (AFR) AF: 0.185 AC: 7688 AN: 41516

American (AMR) AF: 0.481 AC: 7354 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1567 AN: 3468

East Asian (EAS) AF: 0.391 AC: 2017 AN: 5160

South Asian (SAS) AF: 0.382 AC: 1839 AN: 4816

European-Finnish (FIN) AF: 0.394 AC: 4155 AN: 10550

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25919 AN: 67954

Other (OTH) AF: 0.380 AC: 799 AN: 2102

Alfa AF: 0.378 Hom.: 14081

Bravo AF: 0.343

Asia WGS AF: 0.403 AC: 1398 AN: 3470

ClinVar

ClinVar submissions as Germline

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	-0.83
CADD	Benign	1.4
DANN	Benign	0.81
PhyloP100		-0.43
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: rs699186; hg19: chr6-76625079; COSMIC: COSV64121114; COSMIC: COSV64121114;