19-50268255-G-T

Variant names:

• chr19-50268255-G-T
• rs113993956
• NM_001145809.2:c.2921G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001145809.2(MYH14):​c.2921G>T​(p.Arg974Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R974C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.04
• Publications: 18 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-50268255-G-T is Pathogenic according to our data. Variant chr19-50268255-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2921G>T	p.Arg974Leu	missense	Exon 24 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.2822G>T	p.Arg941Leu	missense	Exon 23 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.2798G>T	p.Arg933Leu	missense	Exon 22 of 41	NP_079005.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.2921G>T	p.Arg974Leu	missense	Exon 24 of 43	ENSP00000493594.1
	MYH14	ENST00000599920.5	TSL:1	c.2822G>T	p.Arg941Leu	missense	Exon 23 of 24	ENSP00000469573.1
	MYH14	ENST00000425460.6	TSL:5	c.2822G>T	p.Arg941Leu	missense	Exon 23 of 42	ENSP00000407879.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418752 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 701990

African (AFR) AF: 0.00 AC: 0 AN: 32312

American (AMR) AF: 0.00 AC: 0 AN: 38582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25322

East Asian (EAS) AF: 0.00 AC: 0 AN: 37088

South Asian (SAS) AF: 0.00 AC: 0 AN: 80490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090536

Other (OTH) AF: 0.00 AC: 0 AN: 58828

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000449 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Pathogenic:2

Aug 18, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant has been previously reported as disease-causing and was identified in a 12 yo male with axonal neuropathy and neurosensory hearing loss.

Jun 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Nov 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect due to impairments in mitochondrial fission (Almutawa et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21480433, 31231018, 27875632, 26257172, 28708278)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.012
Eigen_PC	Benign	0.040
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.66
Sift	Benign	0.053	T
Sift4G	Benign	0.19	T
Polyphen		0.51	P
Vest4		0.77
MutPred		0.40		Loss of MoRF binding (P = 0.0176)
MVP		0.98
MPC		0.70
ClinPred		0.96	D
GERP RS		3.9
Varity_R		0.16
gMVP		0.51
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs113993956; hg19: chr19-50771512;