rs34498817

Positions:

• chr19-50231980-C-G
• chr19-50231980-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001145809.2(MYH14):​c.1024C>G​(p.Pro342Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,613,936 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (55 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (56 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.156

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=0.0027463734).
• BP6: Variant 19-50231980-C-G is Benign according to our data. Variant chr19-50231980-C-G is described in ClinVar as [Benign]. Clinvar id is 44043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.1024C>G	p.Pro342Ala	missense_variant	10/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.1024C>G	p.Pro342Ala	missense_variant	10/42		NP_001070654.1
MYH14	NM_024729.4	c.1000C>G	p.Pro334Ala	missense_variant	9/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.1024C>G	p.Pro342Ala	missense_variant	10/43		NM_001145809.2	ENSP00000493594

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2313 AN: 152244 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00382 AC: 952 AN: 248984 Hom.: 23 AF XY: 0.00295 AC XY: 398 AN XY: 135126

Gnomad AFR exome AF: 0.0539

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00159 AC: 2324 AN: 1461574 Hom.: 56 Cov.: 31 AF XY: 0.00137 AC XY: 994 AN XY: 727080

Gnomad4 AFR exome AF: 0.0564

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.00338

GnomAD4 genome AF: 0.0152 AC: 2323 AN: 152362 Hom.: 55 Cov.: 33 AF XY: 0.0147 AC XY: 1099 AN XY: 74512

Gnomad4 AFR AF: 0.0530

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00205 Hom.: 6

Bravo AF: 0.0169

ESP6500AA AF: 0.0462 AC: 185

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.00456 AC: 551

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2018	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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 15, 2022	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Pro342Ala in Exon 10 of MYH14: This variant is not expected to have clinical sig nificance because it has been identified in 4.2% (141/3318) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs34498817). -

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	0.059
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.17	.;.;T;.;T;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.94	.;D;D;.;D;D;.
MetaRNN	Benign	0.0027	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.57	.;.;N;.;.;.;N
MutationTaster	Benign	0.88	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.56	.;N;N;.;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.52	.;T;T;.;.;.;.
Sift4G	Benign	0.83	T;T;T;.;T;T;T
Polyphen		0.062	B;B;B;B;.;B;B
Vest4		0.36
MVP		0.42
MPC		0.45
ClinPred		0.0027	T
GERP RS		3.0
Varity_R		0.065
gMVP		0.11

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: rs34498817; hg19: chr19-50735237;