NM_001145809.2:c.1024C>G

Variant names:

• chr19-50231980-C-G
• rs34498817
• NM_001145809.2:c.1024C>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P342P) has been classified as Likely 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
• Publications: 7 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=0.0027463734).
• BP6: Variant 19-50231980-C-G is Benign according to our data. Variant chr19-50231980-C-G is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	NM_001145809.2	MANE Select	c.1024C>G	p.Pro342Ala	missense	Exon 10 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.1024C>G	p.Pro342Ala	missense	Exon 10 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.1000C>G	p.Pro334Ala	missense	Exon 9 of 41	NP_079005.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.1024C>G	p.Pro342Ala	missense	Exon 10 of 43	ENSP00000493594.1
	MYH14	ENST00000599920.5	TSL:1	c.1024C>G	p.Pro342Ala	missense	Exon 10 of 24	ENSP00000469573.1
	MYH14	ENST00000425460.6	TSL:5	c.1024C>G	p.Pro342Ala	missense	Exon 10 of 42	ENSP00000407879.1

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

GnomAD2 exomes AF: 0.00382 AC: 952 AN: 248984 AF XY: 0.00295

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 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

African (AFR) AF: 0.0564 AC: 1887 AN: 33480

American (AMR) AF: 0.00253 AC: 113 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000809 AC: 90 AN: 1111870

Other (OTH) AF: 0.00338 AC: 204 AN: 60374

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

African (AFR) AF: 0.0530 AC: 2202 AN: 41576

American (AMR) AF: 0.00516 AC: 79 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68036

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

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

Nov 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 15, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 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 v4.9

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
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.57	N
PhyloP100		0.16
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.12
Sift	Benign	0.52	T
Sift4G	Benign	0.83	T
Polyphen		0.062	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
Mutation Taster		=99/1	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: rs34498817; hg19: chr19-50735237;