rs200424400

Positions:

• chr19-50226912-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001145809.2(MYH14):​c.820A>G​(p.Ile274Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000363 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 9.15

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22559306).
• BP6: Variant 19-50226912-A-G is Benign according to our data. Variant chr19-50226912-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178412.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000309 (47/152160) while in subpopulation SAS AF= 0.00083 (4/4820). AF 95% confidence interval is 0.000381. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.820A>G	p.Ile274Val	missense_variant	8/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.820A>G	p.Ile274Val	missense_variant	8/42		NP_001070654.1
MYH14	NM_024729.4	c.796A>G	p.Ile266Val	missense_variant	7/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.820A>G	p.Ile274Val	missense_variant	8/43		NM_001145809.2	ENSP00000493594

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000414 AC: 104 AN: 251194 Hom.: 0 AF XY: 0.000582 AC XY: 79 AN XY: 135788

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000369 AC: 539 AN: 1461600 Hom.: 0 Cov.: 32 AF XY: 0.000462 AC XY: 336 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000294

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000518 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000469 AC: 57

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2017	The p.Ile266Val variant (rs200424400) has not been reported in the medical literature, but it is classified as a variant of uncertain significance in ClinVar (Variant ID: 178412). It has also been previously identified by our laboratory in a 38 year old woman without reported symptoms of hearing loss, and is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.042% (identified in 116 out of 276,962 chromosomes). The isoleucine at codon 266 is highly conserved considering 7 species up to Cow (Alamut software v2.9), and computational analyses suggest that this variant effects the MYH14 protein structure/function (SIFT: damaging, PolyPhen2: possibly damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Ile266Val variant cannot be determined with certainty. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	This variant is associated with the following publications: (PMID: 15015131) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MYH14: BS1, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 07, 2017

The p.Ile274Val variant in MYH14 has been previously reported by our laboratory in 3 individuals with hearing loss. This variant has been identified in 0.1% (17 /16486) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs200424400). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses sugges t that the p.Ile274Val variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, the clinical si gnificance of the p.Ile274Val variant is uncertain. -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

MYH14-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;.;T;.;T;.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;.;D;D;.
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.2	.;.;M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.87	.;N;N;.;.;.;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.016	.;D;D;.;.;.;.
Sift4G	Uncertain	0.031	D;D;D;.;D;D;D
Polyphen		0.97	D;D;D;D;.;D;D
Vest4		0.60
MVP		0.75
MPC		0.66
ClinPred		0.085	T
GERP RS		3.9
Varity_R		0.11
gMVP		0.37

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: rs200424400; hg19: chr19-50730169;