chr19-50259161-A-G

Variant names:

• chr19-50259161-A-G
• rs1651553
• NM_001145809.2:c.2250A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001145809.2(MYH14):​c.2250A>G​(p.Pro750Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,556,696 control chromosomes in the GnomAD database, including 440,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42786 hom., cov: 33)
  • Exomes 𝑓: 0.75 (397456 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.86
• Publications: 26 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-50259161-A-G is Benign according to our data. Variant chr19-50259161-A-G is described in ClinVar as Benign. ClinVar VariationId is 44056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.82 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.2250A>G	p.Pro750Pro	synonymous	Exon 19 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.2151A>G	p.Pro717Pro	synonymous	Exon 18 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.2127A>G	p.Pro709Pro	synonymous	Exon 17 of 41	NP_079005.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.2250A>G	p.Pro750Pro	synonymous	Exon 19 of 43	ENSP00000493594.1
	MYH14	ENST00000599920.5	TSL:1	c.2151A>G	p.Pro717Pro	synonymous	Exon 18 of 24	ENSP00000469573.1
	MYH14	ENST00000425460.6	TSL:5	c.2151A>G	p.Pro717Pro	synonymous	Exon 18 of 42	ENSP00000407879.1

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113719 AN: 152060 Hom.: 42744 Cov.: 33

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.829

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.710

GnomAD2 exomes AF: 0.773 AC: 126223 AN: 163394 AF XY: 0.770

Gnomad AFR exome AF: 0.713

Gnomad AMR exome AF: 0.841

Gnomad ASJ exome AF: 0.663

Gnomad EAS exome AF: 0.837

Gnomad FIN exome AF: 0.826

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.738

GnomAD4 exome AF: 0.751 AC: 1055259 AN: 1404518 Hom.: 397456 Cov.: 59 AF XY: 0.752 AC XY: 521458 AN XY: 693232

African (AFR) AF: 0.706 AC: 22486 AN: 31836

American (AMR) AF: 0.829 AC: 30118 AN: 36326

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 16999 AN: 25292

East Asian (EAS) AF: 0.869 AC: 31529 AN: 36274

South Asian (SAS) AF: 0.783 AC: 62386 AN: 79666

European-Finnish (FIN) AF: 0.821 AC: 40544 AN: 49412

Middle Eastern (MID) AF: 0.713 AC: 4064 AN: 5696

European-Non Finnish (NFE) AF: 0.743 AC: 803894 AN: 1081764

Other (OTH) AF: 0.742 AC: 43239 AN: 58252

GnomAD4 genome AF: 0.748 AC: 113817 AN: 152178 Hom.: 42786 Cov.: 33 AF XY: 0.753 AC XY: 56021 AN XY: 74398

African (AFR) AF: 0.709 AC: 29445 AN: 41504

American (AMR) AF: 0.790 AC: 12056 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2360 AN: 3472

East Asian (EAS) AF: 0.841 AC: 4351 AN: 5176

South Asian (SAS) AF: 0.793 AC: 3827 AN: 4824

European-Finnish (FIN) AF: 0.829 AC: 8792 AN: 10606

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.743 AC: 50496 AN: 68008

Other (OTH) AF: 0.712 AC: 1504 AN: 2112

Alfa AF: 0.740 Hom.: 13606

Bravo AF: 0.742

Asia WGS AF: 0.824 AC: 2865 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

May 09, 2017

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro750Pro in Exon 19 of MYH14: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 28.3% (1016/3590) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1651553).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Autosomal dominant nonsyndromic hearing loss 4A Benign:2

Jan 13, 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.

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.67
PhyloP100		-4.9
Mutation Taster		=94/6	polymorphism (auto)

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: rs1651553; hg19: chr19-50762418; COSMIC: COSV51817800; COSMIC: COSV51817800;