rs28940306

Positions:

• chr19-50271424-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001145809.2(MYH14):​c.3049C>T​(p.Leu1017Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.18

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 19-50271424-C-T is Pathogenic according to our data. Variant chr19-50271424-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2197.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-50271424-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.3049C>T	p.Leu1017Phe	missense_variant	25/43	ENST00000642316.2
MYH14	NM_001077186.2	c.2950C>T	p.Leu984Phe	missense_variant	24/42
MYH14	NM_024729.4	c.2926C>T	p.Leu976Phe	missense_variant	23/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.3049C>T	p.Leu1017Phe	missense_variant	25/43		NM_001145809.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000428 AC: 1 AN: 233784 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126566

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: 0.00000950

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 4A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	0.056
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.58	T
Sift4G	Uncertain	0.0040	D;D;D;.;D;D;D
Polyphen		0.59	P;P;B;P;.;P;B
Vest4		0.81
MutPred		0.71		.;.;Gain of helix (P = 0.0861);.;.;.;Gain of helix (P = 0.0861);
MVP		0.93
MPC		0.44
ClinPred		0.97	D
GERP RS		2.5
Varity_R		0.077
gMVP		0.29

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: rs28940306; hg19: chr19-50774681;