rs4801822

Variant names:

• chr19-50223313-G-A
• rs4801822
• NM_001145809.2:c.657G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50223313-G-A
• chr19-50223313-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001145809.2(MYH14):​c.657G>A​(p.Ala219Ala) 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:10
• Conservation: PhyloP100: -2.92
• Publications: 30 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=-0.58).
• BP6: Variant 19-50223313-G-A is Benign according to our data. Variant chr19-50223313-G-A is described in ClinVar as Benign. ClinVar VariationId is 44079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.657G>A	p.Ala219Ala	synonymous_variant	Exon 5 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.657G>A	p.Ala219Ala	synonymous_variant	Exon 5 of 42		NP_001070654.1
MYH14	NM_024729.4	c.657G>A	p.Ala219Ala	synonymous_variant	Exon 5 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.657G>A	p.Ala219Ala	synonymous_variant	Exon 5 of 43		NM_001145809.2	ENSP00000493594.1

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

GnomAD2 exomes AF: 0.569 AC: 122450 AN: 215144 AF XY: 0.582

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 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

African (AFR) AF: 0.196 AC: 6476 AN: 32980

American (AMR) AF: 0.450 AC: 18169 AN: 40362

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 13552 AN: 25734

East Asian (EAS) AF: 0.637 AC: 24479 AN: 38438

South Asian (SAS) AF: 0.615 AC: 51582 AN: 83904

European-Finnish (FIN) AF: 0.650 AC: 33804 AN: 52044

Middle Eastern (MID) AF: 0.508 AC: 2921 AN: 5746

European-Non Finnish (NFE) AF: 0.650 AC: 715847 AN: 1101166

Other (OTH) AF: 0.593 AC: 35347 AN: 59642

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

African (AFR) AF: 0.208 AC: 8628 AN: 41520

American (AMR) AF: 0.506 AC: 7733 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1851 AN: 3472

East Asian (EAS) AF: 0.578 AC: 2981 AN: 5156

South Asian (SAS) AF: 0.629 AC: 3029 AN: 4816

European-Finnish (FIN) AF: 0.663 AC: 7026 AN: 10596

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.637 AC: 43329 AN: 67974

Other (OTH) AF: 0.511 AC: 1081 AN: 2114

Alfa AF: 0.585 Hom.: 38013

Bravo AF: 0.474

Asia WGS AF: 0.582 AC: 2022 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

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). -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 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:2

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.17
DANN	Benign	0.66
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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