rs4801822

chr19-50223313-G-Achr19-50223313-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001145809.2(MYH14):c.657G>A(p.Ala219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,592,160 control chromosomes in the GnomAD database, including 309,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A219A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.50 (21887 hom., cov: 33)
  • Exomes 𝑓: 0.63 (287982 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.92

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=-0.58).
• BP6: Variant 19-50223313-G-A is Benign according to our data. Variant chr19-50223313-G-A is described in ClinVar as [Benign]. Clinvar id is 44079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50223313-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.657G>A	p.Ala219=	synonymous_variant	5/43	ENST00000642316.2
MYH14	NM_001077186.2	c.657G>A	p.Ala219=	synonymous_variant	5/42
MYH14	NM_024729.4	c.657G>A	p.Ala219=	synonymous_variant	5/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.657G>A	p.Ala219=	synonymous_variant	5/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76331 AN: 152026 Hom.: 21887 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.579

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.511

GnomAD3 exomes AF: 0.569 AC: 122450 AN: 215144 Hom.: 36292 AF XY: 0.582 AC XY: 67689 AN XY: 116368

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.444

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.570

Gnomad SAS exome AF: 0.618

Gnomad FIN exome AF: 0.652

Gnomad NFE exome AF: 0.629

Gnomad OTH exome AF: 0.580

GnomAD4 exome AF: 0.627 AC: 902177 AN: 1440016 Hom.: 287982 Cov.: 51 AF XY: 0.627 AC XY: 448254 AN XY: 714584

Gnomad4 AFR exome AF: 0.196

Gnomad4 AMR exome AF: 0.450

Gnomad4 ASJ exome AF: 0.527

Gnomad4 EAS exome AF: 0.637

Gnomad4 SAS exome AF: 0.615

Gnomad4 FIN exome AF: 0.650

Gnomad4 NFE exome AF: 0.650

Gnomad4 OTH exome AF: 0.593

GnomAD4 genome AF: 0.502 AC: 76338 AN: 152144 Hom.: 21887 Cov.: 33 AF XY: 0.505 AC XY: 37532 AN XY: 74380

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.506

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.578

Gnomad4 SAS AF: 0.629

Gnomad4 FIN AF: 0.663

Gnomad4 NFE AF: 0.637

Gnomad4 OTH AF: 0.511

Alfa AF: 0.589 Hom.: 33866

Bravo AF: 0.474

Asia WGS AF: 0.582 AC: 2022 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ala219Ala in Exon 05 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 36.8% (2569/6986) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs4801822). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal dominant nonsyndromic hearing loss 4A Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.17
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs4801822; hg19: chr19-50726570; COSMIC: COSV51809625;