rs190695624

Positions:

• chr19-50309085-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.5868C>T​(p.Ala1956=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00892 in 1,613,836 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0091 (82 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.87

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 19-50309085-C-T is Benign according to our data. Variant chr19-50309085-C-T is described in ClinVar as [Benign]. Clinvar id is 44076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50309085-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.87 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00685 (1043/152244) while in subpopulation NFE AF= 0.0108 (733/67996). AF 95% confidence interval is 0.0101. There are 5 homozygotes in gnomad4. There are 496 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1043 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.5868C>T	p.Ala1956=	synonymous_variant	42/43	ENST00000642316.2
MYH14	NM_001077186.2	c.5769C>T	p.Ala1923=	synonymous_variant	41/42
MYH14	NM_024729.4	c.5745C>T	p.Ala1915=	synonymous_variant	40/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.5868C>T	p.Ala1956=	synonymous_variant	42/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1043 AN: 152126 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00782 AC: 1947 AN: 248984 Hom.: 13 AF XY: 0.00790 AC XY: 1068 AN XY: 135108

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00333

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00943

GnomAD4 exome AF: 0.00914 AC: 13355 AN: 1461592 Hom.: 82 Cov.: 33 AF XY: 0.00917 AC XY: 6665 AN XY: 727098

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00333

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.000856

Gnomad4 SAS exome AF: 0.00357

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00727

GnomAD4 genome AF: 0.00685 AC: 1043 AN: 152244 Hom.: 5 Cov.: 31 AF XY: 0.00666 AC XY: 496 AN XY: 74432

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0186

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00865 Hom.: 5

Bravo AF: 0.00554

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Apr 30, 2012	Ala1956Ala in Exon 42 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 1.0% (68/6808) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 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	Invitae	Jan 25, 2024	- -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.21
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: rs190695624; hg19: chr19-50812342;