19-50217683-T-C

Variant names:

• chr19-50217683-T-C
• rs34796700
• NM_001145809.2:c.474T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001145809.2(MYH14):​c.474T>C​(p.Ile158Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0404 in 1,613,974 control chromosomes in the GnomAD database, including 1,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (85 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1497 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.32
• Publications: 4 publications found

Genes affected

MYH14 (HGNC:23212): (myosin heavy chain 14) This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

MYH14 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 4A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-50217683-T-C is Benign according to our data. Variant chr19-50217683-T-C is described in ClinVar as Benign. ClinVar VariationId is 44071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0278 (4228/152298) while in subpopulation NFE AF = 0.0443 (3015/68018). AF 95% confidence interval is 0.043. There are 85 homozygotes in GnomAd4. There are 1951 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4228 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145809.2. 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
	MYH14	NM_001145809.2	MANE Select	c.474T>C	p.Ile158Ile	synonymous	Exon 3 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.474T>C	p.Ile158Ile	synonymous	Exon 3 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.474T>C	p.Ile158Ile	synonymous	Exon 3 of 41	NP_079005.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.474T>C	p.Ile158Ile	synonymous	Exon 3 of 43	ENSP00000493594.1
	MYH14	ENST00000599920.5	TSL:1	c.474T>C	p.Ile158Ile	synonymous	Exon 3 of 24	ENSP00000469573.1
	MYH14	ENST00000425460.6	TSL:5	c.474T>C	p.Ile158Ile	synonymous	Exon 3 of 42	ENSP00000407879.1

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4231 AN: 152180 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.00791

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0440

GnomAD2 exomes AF: 0.0286 AC: 7125 AN: 249294 AF XY: 0.0299

Gnomad AFR exome AF: 0.00741

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0220

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0430

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0417 AC: 61020 AN: 1461676 Hom.: 1497 Cov.: 33 AF XY: 0.0413 AC XY: 30016 AN XY: 727122

African (AFR) AF: 0.00660 AC: 221 AN: 33480

American (AMR) AF: 0.0216 AC: 966 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 609 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0221 AC: 1906 AN: 86258

European-Finnish (FIN) AF: 0.0179 AC: 954 AN: 53374

Middle Eastern (MID) AF: 0.0376 AC: 217 AN: 5768

European-Non Finnish (NFE) AF: 0.0483 AC: 53739 AN: 1111864

Other (OTH) AF: 0.0399 AC: 2407 AN: 60374

GnomAD4 genome AF: 0.0278 AC: 4228 AN: 152298 Hom.: 85 Cov.: 32 AF XY: 0.0262 AC XY: 1951 AN XY: 74456

African (AFR) AF: 0.00789 AC: 328 AN: 41572

American (AMR) AF: 0.0286 AC: 438 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5174

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4822

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10622

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0443 AC: 3015 AN: 68018

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0336 Hom.: 52

Bravo AF: 0.0295

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0446

EpiControl AF: 0.0453

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile158Ile in Exon 03 of MYH14: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 4.1% (286/6980) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs34796700).

Dec 06, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:3

Sep 20, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.2
DANN	Benign	0.77
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34796700; hg19: chr19-50720940; COSMIC: COSV107267421;