rs112716976

Variant names:

• chr19-50281720-G-A
• rs112716976
• NM_001145809.2:c.4417G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50281720-G-A
• chr19-50281720-G-C

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.00
• Publications: 6 publications found

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]

MYH14 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 4A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 147 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.4417G>A	p.Val1473Met	missense_variant	Exon 33 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.4318G>A	p.Val1440Met	missense_variant	Exon 32 of 42		NP_001070654.1
MYH14	NM_024729.4	c.4294G>A	p.Val1432Met	missense_variant	Exon 31 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.4417G>A	p.Val1473Met	missense_variant	Exon 33 of 43		NM_001145809.2	ENSP00000493594.1

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

GnomAD2 exomes AF: 0.000434 AC: 105 AN: 241862 AF XY: 0.000407

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 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

African (AFR) AF: 0.00257 AC: 86 AN: 33470

American (AMR) AF: 0.000179 AC: 8 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86224

European-Finnish (FIN) AF: 0.000498 AC: 26 AN: 52258

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.000244 AC: 271 AN: 1111674

Other (OTH) AF: 0.000448 AC: 27 AN: 60332

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

African (AFR) AF: 0.00252 AC: 105 AN: 41588

American (AMR) AF: 0.000457 AC: 7 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000647 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: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH14: BS1, BS2 -

Mar 11, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

MYH14-related disorder Benign:1

Apr 02, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	Benign	0.096
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	.;.;.;T;.;.;T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.39	.;T;T;T;.;T;.;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.69	.;.;.;N;.;.;N;.
PhyloP100		2.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.060	.;.;N;.;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.20	.;.;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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

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