rs112716976

chr19-50281720-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.4417G>A(p.Val1473Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,612,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.00

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=0.014956325).
• BP6: Variant 19-50281720-G-A is Benign according to our data. Variant chr19-50281720-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227579.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 = 0.000965 (147/152372) while in subpopulation AFR AF= 0.00252 (105/41588). AF 95% confidence interval is 0.00213. There are 0 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 147 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.4417G>A	p.Val1473Met	missense_variant	33/43	ENST00000642316.2
MYH14	NM_001077186.2	c.4318G>A	p.Val1440Met	missense_variant	32/42
MYH14	NM_024729.4	c.4294G>A	p.Val1432Met	missense_variant	31/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.4417G>A	p.Val1473Met	missense_variant	33/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.000965 AC: 147 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000434 AC: 105 AN: 241862 Hom.: 0 AF XY: 0.000407 AC XY: 54 AN XY: 132722

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.000609

Gnomad NFE exome AF: 0.000463

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000293 AC: 428 AN: 1460156 Hom.: 0 Cov.: 32 AF XY: 0.000324 AC XY: 235 AN XY: 726400

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000498

Gnomad4 NFE exome AF: 0.000244

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000965 AC: 147 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74516

Gnomad4 AFR AF: 0.00252

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000547 Hom.: 0

Bravo AF: 0.000997

ESP6500AA AF: 0.000763 AC: 3

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.000400 AC: 48

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 08, 2016

p.Val1473Met in exon 33 of MYH14: This variant is not expected to have clinical significance because it has been identified in 0.3% (21/7786) of African chromos omes, including 1 homozygote, by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs112716976). -

MYH14-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2020

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). -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	23
Dann	Uncertain	0.98
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.087	N
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.71	T
Sift4G	Benign	0.21	T;T;T;T;.;T;T;T
Polyphen		1.0	D;.;D;B;D;D;B;.
Vest4		0.28
MVP		0.62
MPC		0.35
ClinPred		0.025	T
GERP RS		2.7
Varity_R		0.041
gMVP		0.12

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: rs112716976; hg19: chr19-50784977; COSMIC: COSV51824503; COSMIC: COSV51824503;