rs73932457

Variant names:

• chr19-50309691-A-T
• rs73932457
• NM_001145809.2:c.6012A>T

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.6012A>T​(p.Leu2004Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,608,952 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (40 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.75

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=-0.62).
• BP6: Variant 19-50309691-A-T is Benign according to our data. Variant chr19-50309691-A-T is described in ClinVar as [Benign]. Clinvar id is 44078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50309691-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1734/151332) while in subpopulation AFR AF= 0.0401 (1649/41132). AF 95% confidence interval is 0.0385. There are 40 homozygotes in gnomad4. There are 810 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1734 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.6012A>T	p.Leu2004Leu	synonymous_variant	Exon 43 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.5913A>T	p.Leu1971Leu	synonymous_variant	Exon 42 of 42		NP_001070654.1
MYH14	NM_024729.4	c.5889A>T	p.Leu1963Leu	synonymous_variant	Exon 41 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.6012A>T	p.Leu2004Leu	synonymous_variant	Exon 43 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1734 AN: 151216 Hom.: 40 Cov.: 30

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00416

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00273 AC: 655 AN: 239628 Hom.: 11 AF XY: 0.00204 AC XY: 265 AN XY: 130126

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000343

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000157

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.00122 AC: 1779 AN: 1457620 Hom.: 30 Cov.: 35 AF XY: 0.00109 AC XY: 793 AN XY: 724664

Gnomad4 AFR exome AF: 0.0412

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00200

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000470

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.00259

GnomAD4 genome AF: 0.0115 AC: 1734 AN: 151332 Hom.: 40 Cov.: 30 AF XY: 0.0110 AC XY: 810 AN XY: 73886

Gnomad4 AFR AF: 0.0401

Gnomad4 AMR AF: 0.00416

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00382 Hom.: 5

Bravo AF: 0.0127

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 12, 2018

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. -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu2004Leu in Exon 43 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 3.5% (115/3332) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs73932457). -

not provided Benign:2

-

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. -

MYH14-related disorder Benign:1

Sep 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs73932457; hg19: chr19-50812948;