19-50263393-C-G

Position:

• chr19-50263393-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145809.2(MYH14):​c.2667C>G​(p.His889Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33409017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.2667C>G	p.His889Gln	missense_variant	22/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.2568C>G	p.His856Gln	missense_variant	21/42		NP_001070654.1
MYH14	NM_024729.4	c.2544C>G	p.His848Gln	missense_variant	20/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.2667C>G	p.His889Gln	missense_variant	22/43		NM_001145809.2	ENSP00000493594

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 07, 2015

The p.His889Gln variant in MYH14 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational p rediction tools and conservation analyses suggest that the p.His889Gln variant m ay not impact the protein, though this information is not predictive enough to r ule out pathogenicity. In summary, the clinical significance of the p.His889Gln variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.45	.;.;T;.;T;.;T
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	.;D;D;.;D;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.3	.;.;L;.;.;.;L
MutationTaster	Benign	0.51	D;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	.;D;.;.;.;.;.
REVEL	Benign	0.096
Sift	Uncertain	0.0010	.;D;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;.;T;D;D
Polyphen		0.30	B;B;B;B;.;B;B
Vest4		0.43
MutPred		0.39		.;.;Loss of ubiquitination at K845 (P = 0.3126);.;.;.;Loss of ubiquitination at K845 (P = 0.3126);
MVP		0.60
MPC		0.54
ClinPred		0.65	D
GERP RS		2.4
Varity_R		0.10
gMVP		0.68

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: rs876657872; hg19: chr19-50766650;