rs10419343

chr19-50293684-G-Achr19-50293684-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001145809.2(MYH14):c.5466G>A(p.Leu1822=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,572,288 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (19 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (33 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.598

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 19-50293684-G-A is Benign according to our data. Variant chr19-50293684-G-A is described in ClinVar as [Benign]. Clinvar id is 164206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50293684-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.598 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00975 (1485/152326) while in subpopulation AFR AF= 0.0332 (1380/41562). AF 95% confidence interval is 0.0317. There are 19 homozygotes in gnomad4. There are 725 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1474 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.5466G>A	p.Leu1822=	synonymous_variant	39/43	ENST00000642316.2
MYH14	NM_001077186.2	c.5367G>A	p.Leu1789=	synonymous_variant	38/42
MYH14	NM_024729.4	c.5343G>A	p.Leu1781=	synonymous_variant	37/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.5466G>A	p.Leu1822=	synonymous_variant	39/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.00968 AC: 1474 AN: 152208 Hom.: 19 Cov.: 34

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00314 AC: 679 AN: 216424 Hom.: 14 AF XY: 0.00263 AC XY: 305 AN XY: 115782

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.00379

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000403

Gnomad OTH exome AF: 0.000975

GnomAD4 exome AF: 0.00126 AC: 1788 AN: 1419962 Hom.: 33 Cov.: 47 AF XY: 0.00120 AC XY: 840 AN XY: 701346

Gnomad4 AFR exome AF: 0.0365

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.00338

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000799

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00975 AC: 1485 AN: 152326 Hom.: 19 Cov.: 34 AF XY: 0.00973 AC XY: 725 AN XY: 74474

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00421 Hom.: 5

Bravo AF: 0.0111

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Leu1822Leu in Exon 39 of MYH14: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 2.8% (104/3710) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs10419343). -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.39
Cadd	Benign	5.5
Dann	Benign	0.84

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: rs10419343; hg19: chr19-50796941;