rs378811

Positions:

• chr19-50257459-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001145809.2(MYH14):​c.2205C>G​(p.Arg735=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 1,602,566 control chromosomes in the GnomAD database, including 143,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11520 hom., cov: 32)
  • Exomes 𝑓: 0.42 (131890 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.21

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 19-50257459-C-G is Benign according to our data. Variant chr19-50257459-C-G is described in ClinVar as [Benign]. Clinvar id is 44055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50257459-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.2205C>G	p.Arg735=	synonymous_variant	18/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.2106C>G	p.Arg702=	synonymous_variant	17/42		NP_001070654.1
MYH14	NM_024729.4	c.2082C>G	p.Arg694=	synonymous_variant	16/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.2205C>G	p.Arg735=	synonymous_variant	18/43		NM_001145809.2	ENSP00000493594

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58212 AN: 151958 Hom.: 11525 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.408

GnomAD3 exomes AF: 0.382 AC: 88552 AN: 231796 Hom.: 17400 AF XY: 0.390 AC XY: 48875 AN XY: 125346

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.486

Gnomad EAS exome AF: 0.387

Gnomad SAS exome AF: 0.377

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.430

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.424 AC: 614762 AN: 1450490 Hom.: 131890 Cov.: 50 AF XY: 0.424 AC XY: 305183 AN XY: 720294

Gnomad4 AFR exome AF: 0.312

Gnomad4 AMR exome AF: 0.261

Gnomad4 ASJ exome AF: 0.482

Gnomad4 EAS exome AF: 0.349

Gnomad4 SAS exome AF: 0.387

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.440

Gnomad4 OTH exome AF: 0.417

GnomAD4 genome AF: 0.383 AC: 58220 AN: 152076 Hom.: 11520 Cov.: 32 AF XY: 0.378 AC XY: 28091 AN XY: 74340

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.479

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.373

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.409

Alfa AF: 0.428 Hom.: 4659

Bravo AF: 0.379

Asia WGS AF: 0.335 AC: 1169 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Arg735Arg in Exon 18 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 42.5% (2938/6920) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs378811). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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	- -

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	-0.28
CADD	Benign	11
DANN	Benign	0.82

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: rs378811; hg19: chr19-50760716; COSMIC: COSV51816085; COSMIC: COSV51816085;