rs35453633

Positions:

• chr19-50286538-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.4596C>T​(p.Ala1532=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,613,374 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1532A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.75

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 (MetaRNN=0.0039724708).
• BP6: Variant 19-50286538-C-T is Benign according to our data. Variant chr19-50286538-C-T is described in ClinVar as [Benign]. Clinvar id is 178618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50286538-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1741/152300) while in subpopulation AFR AF= 0.0396 (1645/41554). AF 95% confidence interval is 0.038. There are 40 homozygotes in gnomad4. There are 831 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1741 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.4596C>T	p.Ala1532=	synonymous_variant	34/43	ENST00000642316.2
MYH14	NM_001077186.2	c.4497C>T	p.Ala1499=	synonymous_variant	33/42
MYH14	NM_024729.4	c.4473C>T	p.Ala1491=	synonymous_variant	32/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.4596C>T	p.Ala1532=	synonymous_variant	34/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1743 AN: 152182 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00301 AC: 740 AN: 245672 Hom.: 11 AF XY: 0.00245 AC XY: 328 AN XY: 133662

Gnomad AFR exome AF: 0.0414

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000628

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00117 AC: 1710 AN: 1461074 Hom.: 28 Cov.: 31 AF XY: 0.00101 AC XY: 731 AN XY: 726742

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000535

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000738

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.0114 AC: 1741 AN: 152300 Hom.: 40 Cov.: 33 AF XY: 0.0112 AC XY: 831 AN XY: 74480

Gnomad4 AFR AF: 0.0396

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00629 Hom.: 9

Bravo AF: 0.0130

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0382 AC: 158

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00368 AC: 445

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ala1532Ala in Exon 34 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 3.6% (124/3456) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs35453633). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 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:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 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_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.7
DANN	Benign	0.72
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0040	T
MutationTaster	Benign	1.0	D;D;D;D
Sift4G	Benign	0.60	T
Vest4		0.091
MVP		0.24
GERP RS		-9.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35453633; hg19: chr19-50789795;