rs727503230

Positions:

• chr19-50309176-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001145809.2(MYH14):​c.5959C>T​(p.Arg1987*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYH14 NM_001145809.2 stop_gained, splice_region
• Scores: Splicing: ADA: 0.3005
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.54

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0249 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.5959C>T	p.Arg1987*	stop_gained, splice_region_variant	42/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.5860C>T	p.Arg1954*	stop_gained, splice_region_variant	41/42		NP_001070654.1
MYH14	NM_024729.4	c.5836C>T	p.Arg1946*	stop_gained, splice_region_variant	40/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.5959C>T	p.Arg1987*	stop_gained, splice_region_variant	42/43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461532 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727068

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 17, 2023	Variant summary: MYH14 c.5836C>T (p.Arg1946X) results in a premature termination codon which is predicted to cause a truncation of the encoded protein, but is not expected to result in nonsense mediated decay. The variant was absent in 249144 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5836C>T in individuals affected with Autosomal Dominant Deafness and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 25, 2013	Variant classified as Uncertain Significance - Favor Pathogenic. The Arg1987X va riant in MYH14 has not been previously reported in individuals with hearing loss or in large population studies. This nonsense variant leads to a premature term ination codon at position 1987 which is 50 amino acid positions upstream of the canonical termination codon. However, the truncation occurs within 50 nucleotide s of the terminal exon-exon junction, and nonsense mediated decay may not occur (Zhang 1998). Therefore, the impact of the variant on the normal function of the protein cannot be predicted. In summary, the clinical significance of this vari ant cannot be determined with certainty; however due to the fact that the varian t is predicted to result in a truncated protein, we would lean towards a more li kely pathogenic role. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.80
GERP RS		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.30
dbscSNV1_RF	Benign	0.54
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: rs727503230; hg19: chr19-50812433;