rs3745509

Variant names:

• chr19-50293648-G-A
• rs3745509
• NM_001145809.2:c.5430G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50293648-G-A
• chr19-50293648-G-C

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.5430G>A​(p.Ser1810Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,609,188 control chromosomes in the GnomAD database, including 442,992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (34886 hom., cov: 32)
  • Exomes 𝑓: 0.74 (408106 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.92
• Publications: 23 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=-0.7).
• BP6: Variant 19-50293648-G-A is Benign according to our data. Variant chr19-50293648-G-A is described in ClinVar as Benign. ClinVar VariationId is 44075.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 (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.5430G>A	p.Ser1810Ser	synonymous_variant	Exon 39 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.5331G>A	p.Ser1777Ser	synonymous_variant	Exon 38 of 42		NP_001070654.1
MYH14	NM_024729.4	c.5307G>A	p.Ser1769Ser	synonymous_variant	Exon 37 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.5430G>A	p.Ser1810Ser	synonymous_variant	Exon 39 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.652 AC: 99057 AN: 151988 Hom.: 34866 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.763

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.677

GnomAD2 exomes AF: 0.757 AC: 185859 AN: 245644 AF XY: 0.760

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.863

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.932

Gnomad FIN exome AF: 0.768

Gnomad NFE exome AF: 0.748

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.745 AC: 1085114 AN: 1457082 Hom.: 408106 Cov.: 51 AF XY: 0.747 AC XY: 540958 AN XY: 724632

African (AFR) AF: 0.351 AC: 11730 AN: 33390

American (AMR) AF: 0.852 AC: 37681 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 18374 AN: 25694

East Asian (EAS) AF: 0.910 AC: 36096 AN: 39678

South Asian (SAS) AF: 0.785 AC: 67086 AN: 85484

European-Finnish (FIN) AF: 0.765 AC: 40713 AN: 53220

Middle Eastern (MID) AF: 0.730 AC: 4097 AN: 5614

European-Non Finnish (NFE) AF: 0.744 AC: 825837 AN: 1109668

Other (OTH) AF: 0.723 AC: 43500 AN: 60126

GnomAD4 genome AF: 0.652 AC: 99106 AN: 152106 Hom.: 34886 Cov.: 32 AF XY: 0.660 AC XY: 49066 AN XY: 74358

African (AFR) AF: 0.362 AC: 14992 AN: 41452

American (AMR) AF: 0.770 AC: 11771 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 2505 AN: 3466

East Asian (EAS) AF: 0.924 AC: 4788 AN: 5184

South Asian (SAS) AF: 0.776 AC: 3742 AN: 4820

European-Finnish (FIN) AF: 0.763 AC: 8090 AN: 10598

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.750 AC: 50980 AN: 67972

Other (OTH) AF: 0.680 AC: 1439 AN: 2116

Alfa AF: 0.715 Hom.: 134935

Bravo AF: 0.640

Asia WGS AF: 0.831 AC: 2890 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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. -

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Clinical Genetics, Academic Medical Center

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

Ser1810Ser 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 36.9% (1373/3716) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3745509). -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Autosomal dominant nonsyndromic hearing loss 4A Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

not provided Benign:2

Feb 03, 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

- -

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	-0.70
CADD	Benign	0.027
DANN	Benign	0.74
PhyloP100		-2.9
Mutation Taster		=90/10	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: rs3745509; hg19: chr19-50796905; COSMIC: COSV108050230;