chr19-50249792-T-C

Position:

• chr19-50249792-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001145809.2(MYH14):​c.1625T>C​(p.Leu542Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L542R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.12

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.1625T>C	p.Leu542Pro	missense_variant	14/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.1625T>C	p.Leu542Pro	missense_variant	14/42		NP_001070654.1
MYH14	NM_024729.4	c.1601T>C	p.Leu534Pro	missense_variant	13/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.1625T>C	p.Leu542Pro	missense_variant	14/43		NM_001145809.2	ENSP00000493594

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251412 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;.;D;.;D;.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	.;D;D;.;D;D;.
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	.;.;M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.6	.;D;D;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	.;D;D;.;.;.;.
Sift4G	Uncertain	0.051	T;T;T;.;D;T;T
Polyphen		1.0	D;D;D;P;.;P;D
Vest4		0.88
MutPred		0.73		.;.;Gain of relative solvent accessibility (P = 0.1571);.;.;.;Gain of relative solvent accessibility (P = 0.1571);
MVP		0.92
MPC		1.7
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.83
gMVP		0.90

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: rs727504564; hg19: chr19-50753049;