19-50268255-G-T

Variant summary

Our verdict is Pathogenic. Variant got 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. R974H) has been classified as Likely benign.

• 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

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 Pathogenic. Variant got 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 id is 30739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50268255-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.2921G>T	p.Arg974Leu	missense_variant	24/43	ENST00000642316.2
MYH14	NM_001077186.2	c.2822G>T	p.Arg941Leu	missense_variant	23/42
MYH14	NM_024729.4	c.2798G>T	p.Arg933Leu	missense_variant	22/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.2921G>T	p.Arg974Leu	missense_variant	24/43		NM_001145809.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2011	- -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Aug 18, 2015	This variant has been previously reported as disease-causing and was identified in a 12 yo male with axonal neuropathy and neurosensory hearing loss. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2022

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 v4.3

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
Eigen	Benign	-0.012
Eigen_PC	Benign	0.040
FATHMM_MKL	Benign	0.56	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
Sift4G	Benign	0.19	T;T;T;.;T;T;T
Polyphen		0.51	P;P;B;B;.;B;B
Vest4		0.77
MutPred		0.40		.;.;Loss of MoRF binding (P = 0.0176);.;.;.;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

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: rs113993956; hg19: chr19-50771512;