rs3745504

chr19-50268352-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001145809.2(MYH14):c.3018G>A(p.Leu1006=) variant causes a synonymous change. The variant allele was found at a frequency of 0.55 in 1,572,796 control chromosomes in the GnomAD database, including 240,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21810 hom., cov: 32)
  • Exomes 𝑓: 0.55 (218901 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.03

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-50268352-G-A is Benign according to our data. Variant chr19-50268352-G-A is described in ClinVar as [Benign]. Clinvar id is 44062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50268352-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.3018G>A	p.Leu1006=	synonymous_variant	24/43	ENST00000642316.2
MYH14	NM_001077186.2	c.2919G>A	p.Leu973=	synonymous_variant	23/42
MYH14	NM_024729.4	c.2895G>A	p.Leu965=	synonymous_variant	22/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.3018G>A	p.Leu1006=	synonymous_variant	24/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80536 AN: 151878 Hom.: 21795 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.543

GnomAD3 exomes AF: 0.559 AC: 103065 AN: 184514 Hom.: 29669 AF XY: 0.550 AC XY: 54420 AN XY: 98952

Gnomad AFR exome AF: 0.455

Gnomad AMR exome AF: 0.743

Gnomad ASJ exome AF: 0.455

Gnomad EAS exome AF: 0.401

Gnomad SAS exome AF: 0.446

Gnomad FIN exome AF: 0.596

Gnomad NFE exome AF: 0.570

Gnomad OTH exome AF: 0.573

GnomAD4 exome AF: 0.552 AC: 783953 AN: 1420800 Hom.: 218901 Cov.: 58 AF XY: 0.548 AC XY: 385438 AN XY: 702904

Gnomad4 AFR exome AF: 0.440

Gnomad4 AMR exome AF: 0.727

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.589

Gnomad4 NFE exome AF: 0.563

Gnomad4 OTH exome AF: 0.538

GnomAD4 genome AF: 0.530 AC: 80579 AN: 151996 Hom.: 21810 Cov.: 32 AF XY: 0.534 AC XY: 39695 AN XY: 74298

Gnomad4 AFR AF: 0.444

Gnomad4 AMR AF: 0.670

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.440

Gnomad4 FIN AF: 0.596

Gnomad4 NFE AF: 0.561

Gnomad4 OTH AF: 0.536

Alfa AF: 0.551 Hom.: 35464

Bravo AF: 0.534

Asia WGS AF: 0.417 AC: 1447 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Leu1006Leu in Exon 24 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 47.3% (1690/3572) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3745504). -
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. -

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	-0.46
Cadd	Benign	7.4
Dann	Benign	0.94

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: rs3745504; hg19: chr19-50771609; COSMIC: COSV51811351;