rs1651553

chr19-50259161-A-G

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.2250A>G(p.Pro750=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,556,696 control chromosomes in the GnomAD database, including 440,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42786 hom., cov: 33)
  • Exomes 𝑓: 0.75 (397456 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.86

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=-0.9).
• BP6: Variant 19-50259161-A-G is Benign according to our data. Variant chr19-50259161-A-G is described in ClinVar as [Benign]. Clinvar id is 44056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50259161-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.2250A>G	p.Pro750=	synonymous_variant	19/43	ENST00000642316.2
MYH14	NM_001077186.2	c.2151A>G	p.Pro717=	synonymous_variant	18/42
MYH14	NM_024729.4	c.2127A>G	p.Pro709=	synonymous_variant	17/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.2250A>G	p.Pro750=	synonymous_variant	19/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113719 AN: 152060 Hom.: 42744 Cov.: 33

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.829

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.710

GnomAD3 exomes AF: 0.773 AC: 126223 AN: 163394 Hom.: 49073 AF XY: 0.770 AC XY: 67159 AN XY: 87252

Gnomad AFR exome AF: 0.713

Gnomad AMR exome AF: 0.841

Gnomad ASJ exome AF: 0.663

Gnomad EAS exome AF: 0.837

Gnomad SAS exome AF: 0.788

Gnomad FIN exome AF: 0.826

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.738

GnomAD4 exome AF: 0.751 AC: 1055259 AN: 1404518 Hom.: 397456 Cov.: 59 AF XY: 0.752 AC XY: 521458 AN XY: 693232

Gnomad4 AFR exome AF: 0.706

Gnomad4 AMR exome AF: 0.829

Gnomad4 ASJ exome AF: 0.672

Gnomad4 EAS exome AF: 0.869

Gnomad4 SAS exome AF: 0.783

Gnomad4 FIN exome AF: 0.821

Gnomad4 NFE exome AF: 0.743

Gnomad4 OTH exome AF: 0.742

GnomAD4 genome AF: 0.748 AC: 113817 AN: 152178 Hom.: 42786 Cov.: 33 AF XY: 0.753 AC XY: 56021 AN XY: 74398

Gnomad4 AFR AF: 0.709

Gnomad4 AMR AF: 0.790

Gnomad4 ASJ AF: 0.680

Gnomad4 EAS AF: 0.841

Gnomad4 SAS AF: 0.793

Gnomad4 FIN AF: 0.829

Gnomad4 NFE AF: 0.743

Gnomad4 OTH AF: 0.712

Alfa AF: 0.740 Hom.: 13606

Bravo AF: 0.742

Asia WGS AF: 0.824 AC: 2865 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro750Pro in Exon 19 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 28.3% (1016/3590) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1651553). -
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 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	-0.90
Cadd	Benign	1.8
Dann	Benign	0.67

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: rs1651553; hg19: chr19-50762418; COSMIC: COSV51817800; COSMIC: COSV51817800;