rs3745509

chr19-50293648-G-Achr19-50293648-G-C

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.5430G>A(p.Ser1810=) 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: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=-0.7).
• BP6: Variant 19-50293648-G-A is Benign according to our data. Variant chr19-50293648-G-A is described in ClinVar as [Benign]. Clinvar id is 44075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50293648-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
MYH14	NM_001145809.2	c.5430G>A	p.Ser1810=	synonymous_variant	39/43	ENST00000642316.2
MYH14	NM_001077186.2	c.5331G>A	p.Ser1777=	synonymous_variant	38/42
MYH14	NM_024729.4	c.5307G>A	p.Ser1769=	synonymous_variant	37/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.5430G>A	p.Ser1810=	synonymous_variant	39/43		NM_001145809.2

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

GnomAD3 exomes AF: 0.757 AC: 185859 AN: 245644 Hom.: 72171 AF XY: 0.760 AC XY: 100984 AN XY: 132944

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 SAS exome AF: 0.784

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

Gnomad4 AFR exome AF: 0.351

Gnomad4 AMR exome AF: 0.852

Gnomad4 ASJ exome AF: 0.715

Gnomad4 EAS exome AF: 0.910

Gnomad4 SAS exome AF: 0.785

Gnomad4 FIN exome AF: 0.765

Gnomad4 NFE exome AF: 0.744

Gnomad4 OTH exome AF: 0.723

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

Gnomad4 AFR AF: 0.362

Gnomad4 AMR AF: 0.770

Gnomad4 ASJ AF: 0.723

Gnomad4 EAS AF: 0.924

Gnomad4 SAS AF: 0.776

Gnomad4 FIN AF: 0.763

Gnomad4 NFE AF: 0.750

Gnomad4 OTH AF: 0.680

Alfa AF: 0.732 Hom.: 94933

Bravo AF: 0.640

Asia WGS AF: 0.831 AC: 2890 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	PreventionGenetics, part of Exact Sciences	-	- -
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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal dominant nonsyndromic hearing loss 4A Benign:2

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. -
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	-0.70
Cadd	Benign	0.027
Dann	Benign	0.74

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: rs3745509; hg19: chr19-50796905;