chr19-50276853-C-A

Position:

• chr19-50276853-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145809.2(MYH14):​c.3777C>A​(p.His1259Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,358,318 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H1259H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22

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 2 ACMG points.

• 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.3777C>A	p.His1259Gln	missense_variant	29/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.3678C>A	p.His1226Gln	missense_variant	28/42		NP_001070654.1
MYH14	NM_024729.4	c.3654C>A	p.His1218Gln	missense_variant	27/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.3777C>A	p.His1259Gln	missense_variant	29/43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246582 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1358318 Hom.: 0 Cov.: 43 AF XY: 0.00000148 AC XY: 1 AN XY: 674810

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: 9.53e-7

Gnomad4 OTH exome AF: 0.0000188

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.3
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	.;.;D;.;.;D;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.79	.;T;T;.;T;.;T
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.69	.;.;N;.;.;N;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.8	.;D;.;.;.;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.023	.;D;.;.;.;.;.
Sift4G	Benign	0.062	T;T;T;.;T;T;T
Polyphen		0.99	D;D;D;D;D;D;.
Vest4		0.41
MutPred		0.66		.;.;Gain of MoRF binding (P = 0.1325);.;.;Gain of MoRF binding (P = 0.1325);.;
MVP		0.82
MPC		0.23
ClinPred		0.51	D
GERP RS		-5.9
Varity_R		0.069
gMVP		0.47

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: rs371116668; hg19: chr19-50780110;