19-50217683-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 44071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50217683-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4228 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.474T>C	p.Ile158Ile	synonymous_variant	Exon 3 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.474T>C	p.Ile158Ile	synonymous_variant	Exon 3 of 42		NP_001070654.1
MYH14	NM_024729.4	c.474T>C	p.Ile158Ile	synonymous_variant	Exon 3 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.474T>C	p.Ile158Ile	synonymous_variant	Exon 3 of 43		NM_001145809.2	ENSP00000493594.1

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

GnomAD3 exomes AF: 0.0286 AC: 7125 AN: 249294 Hom.: 150 AF XY: 0.0299 AC XY: 4043 AN XY: 135230

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 SAS exome AF: 0.0211

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

Gnomad4 AFR exome AF: 0.00660

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.0233

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0221

Gnomad4 FIN exome AF: 0.0179

Gnomad4 NFE exome AF: 0.0483

Gnomad4 OTH exome AF: 0.0399

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

Gnomad4 AFR AF: 0.00789

Gnomad4 AMR AF: 0.0286

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.0443

Gnomad4 OTH AF: 0.0430

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Sep 20, 2018

Athena Diagnostics

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.2
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs34796700; hg19: chr19-50720940;