19-50226912-A-T

Variant names:

• chr19-50226912-A-T
• rs200424400
• NM_001145809.2:c.820A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001145809.2(MYH14):​c.820A>T​(p.Ile274Phe) variant causes a missense change involving the alteration of a conserved nucleotide. 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. I274V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.15
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 4A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.820A>T	p.Ile274Phe	missense_variant	Exon 8 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.820A>T	p.Ile274Phe	missense_variant	Exon 8 of 42		NP_001070654.1
MYH14	NM_024729.4	c.796A>T	p.Ile266Phe	missense_variant	Exon 7 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.820A>T	p.Ile274Phe	missense_variant	Exon 8 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;.;D;.;D;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;D;.;D;D;.
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.0	.;.;M;.;.;.;M
PhyloP100		9.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	.;D;D;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;D;D;D
Polyphen		1.0	D;D;D;D;.;D;D
Vest4		0.91
MutPred		0.82		.;.;Loss of MoRF binding (P = 0.1039);.;.;.;Loss of MoRF binding (P = 0.1039);
MVP		0.90
MPC		1.6
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.49
gMVP		0.80
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs200424400; hg19: chr19-50730169;