rs138987081

Positions:

• chr19-50268175-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001145809.2(MYH14):​c.2841C>T​(p.Arg947=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,547,272 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 33)
  • Exomes 𝑓: 0.014 (169 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.72

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=-0.55).
• BP6: Variant 19-50268175-C-T is Benign according to our data. Variant chr19-50268175-C-T is described in ClinVar as [Benign]. Clinvar id is 44061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50268175-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1558/152340) while in subpopulation NFE AF= 0.0152 (1034/68038). AF 95% confidence interval is 0.0144. There are 14 homozygotes in gnomad4. There are 748 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1558 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.2841C>T	p.Arg947=	synonymous_variant	24/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.2742C>T	p.Arg914=	synonymous_variant	23/42		NP_001070654.1
MYH14	NM_024729.4	c.2718C>T	p.Arg906=	synonymous_variant	22/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.2841C>T	p.Arg947=	synonymous_variant	24/43		NM_001145809.2	ENSP00000493594

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1558 AN: 152222 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0100 AC: 1529 AN: 152730 Hom.: 11 AF XY: 0.0102 AC XY: 828 AN XY: 81194

Gnomad AFR exome AF: 0.00274

Gnomad AMR exome AF: 0.00847

Gnomad ASJ exome AF: 0.00282

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0140 AC: 19586 AN: 1394932 Hom.: 169 Cov.: 34 AF XY: 0.0139 AC XY: 9541 AN XY: 688116

Gnomad4 AFR exome AF: 0.00165

Gnomad4 AMR exome AF: 0.00888

Gnomad4 ASJ exome AF: 0.00262

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00449

Gnomad4 FIN exome AF: 0.0225

Gnomad4 NFE exome AF: 0.0157

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0102 AC: 1558 AN: 152340 Hom.: 14 Cov.: 33 AF XY: 0.0100 AC XY: 748 AN XY: 74490

Gnomad4 AFR AF: 0.00269

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.0115 Hom.: 4

Bravo AF: 0.00942

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MYH14: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2018	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	Apr 30, 2012	Arg947Arg in Exon 24 of MYH14: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 1.3% (86/6654) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs138987081). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 05, 2014	- -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.4
DANN	Benign	0.85

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: rs138987081; hg19: chr19-50771432;