NM_004999.4:c.1120T>C

Variant names:

• chr6-75855180-T-C
• rs61732664
• NM_004999.4:c.1120T>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.1120T>C​(p.Tyr374His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,612,678 control chromosomes in the GnomAD database, including 363 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (321 hom.)
• Consequence: MYO6 NM_004999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.50
• 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: 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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020512044).
• BP6: Variant 6-75855180-T-C is Benign according to our data. Variant chr6-75855180-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0593 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.1120T>C	p.Tyr374His	missense	Exon 12 of 35	NP_004990.3
	MYO6	NM_001368865.1		c.1120T>C	p.Tyr374His	missense	Exon 12 of 36	NP_001355794.1	A0A590UJ40
	MYO6	NM_001368866.1		c.1120T>C	p.Tyr374His	missense	Exon 12 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.1120T>C	p.Tyr374His	missense	Exon 12 of 35	ENSP00000358994.3	Q9UM54-1
	MYO6	ENST00000615563.4	TSL:1	c.1120T>C	p.Tyr374His	missense	Exon 11 of 32	ENSP00000478013.1	Q9UM54-2
	MYO6	ENST00000664640.1		c.1120T>C	p.Tyr374His	missense	Exon 12 of 36	ENSP00000499278.1	A0A590UJ40

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1148 AN: 152190 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0621

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00538

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0172 AC: 4306 AN: 250720 AF XY: 0.0130

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00567

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.00377 AC: 5502 AN: 1460370 Hom.: 321 Cov.: 31 AF XY: 0.00320 AC XY: 2327 AN XY: 726536

African (AFR) AF: 0.00168 AC: 56 AN: 33424

American (AMR) AF: 0.111 AC: 4933 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00527 AC: 209 AN: 39634

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000693 AC: 77 AN: 1110914

Other (OTH) AF: 0.00353 AC: 213 AN: 60326

GnomAD4 genome AF: 0.00760 AC: 1157 AN: 152308 Hom.: 42 Cov.: 32 AF XY: 0.00827 AC XY: 616 AN XY: 74482

African (AFR) AF: 0.00332 AC: 138 AN: 41586

American (AMR) AF: 0.0626 AC: 957 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00539 AC: 28 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68006

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00216 Hom.: 20

Bravo AF: 0.0130

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0128 AC: 1557

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 22 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 37 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 37;C2931767:Autosomal dominant nonsyndromic hearing loss 22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.045	N
PhyloP100		1.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.28
Sift	Benign	0.53	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.034
MPC		0.34
ClinPred		0.0075	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61732664; hg19: chr6-76564897;