rs140118363

chr19-50286627-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145809.2(MYH14):c.4685G>A(p.Arg1562Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,596,622 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1562W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.85

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011157781).
• BP6: Variant 19-50286627-G-A is Benign according to our data. Variant chr19-50286627-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00147 (224/152318) while in subpopulation AFR AF= 0.005 (208/41566). AF 95% confidence interval is 0.00445. There are 0 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 224 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.4685G>A	p.Arg1562Gln	missense_variant	34/43	ENST00000642316.2
MYH14	NM_001077186.2	c.4586G>A	p.Arg1529Gln	missense_variant	33/42
MYH14	NM_024729.4	c.4562G>A	p.Arg1521Gln	missense_variant	32/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.4685G>A	p.Arg1562Gln	missense_variant	34/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000368 AC: 79 AN: 214688 Hom.: 0 AF XY: 0.000275 AC XY: 32 AN XY: 116474

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0000995

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000631

Gnomad SAS exome AF: 0.0000370

Gnomad FIN exome AF: 0.0000545

Gnomad NFE exome AF: 0.0000312

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.000136 AC: 196 AN: 1444304 Hom.: 1 Cov.: 31 AF XY: 0.000114 AC XY: 82 AN XY: 716710

Gnomad4 AFR exome AF: 0.00463

Gnomad4 AMR exome AF: 0.000145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.000251

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00142 AC XY: 106 AN XY: 74470

Gnomad4 AFR AF: 0.00500

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000337 Hom.: 0

Bravo AF: 0.00162

ESP6500AA AF: 0.00471 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000414 AC: 50

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 24, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 05, 2017	p.Arg1562Gln in Exon 34 of MYH14: This variant is not expected to have clinical significance because it has been identified in 0.6% (116/20972) of African chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs140118363). -

MYH14-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2019

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

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.49	D
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.77	T
Sift4G	Uncertain	0.010	D;T;D;D;.;D;D
Polyphen		1.0	D;.;D;D;D;D;D
Vest4		0.42
MVP		0.84
MPC		0.68
ClinPred		0.082	T
GERP RS		4.5
Varity_R		0.17
gMVP		0.40

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: rs140118363; hg19: chr19-50789884;