chr19-50232051-C-A

Variant names:

• chr19-50232051-C-A
• rs727505251
• NM_001145809.2:c.1095C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145809.2(MYH14):​c.1095C>A​(p.Phe365Leu) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.170
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19861981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.1095C>A	p.Phe365Leu	missense_variant	Exon 10 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.1095C>A	p.Phe365Leu	missense_variant	Exon 10 of 42		NP_001070654.1
MYH14	NM_024729.4	c.1071C>A	p.Phe357Leu	missense_variant	Exon 9 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.1095C>A	p.Phe365Leu	missense_variant	Exon 10 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Phe365Leu varia nt in MYH14 has not been previously reported in individuals with hearing loss or in large populations studies. The phenylalanine (Phe) at position 365 is not c onserved in mammals or evolutionary distant species, with rat and mouse having a leucine (Leu) at this position, raising the possibility that a change at this p osition may be tolerated. Additional computational prediction tools suggest that the Phe365Leu variant may not impact the protein, though this information is no t predictive enough to rule out pathogenicity. In summary, while the clinical si gnificance of the Phe365Leu variant is uncertain, these data suggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	.;.;T;.;T;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.84	.;T;T;.;D;T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Benign	1.5	.;.;L;.;.;.;L
PhyloP100		0.17
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	.;N;N;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.23	.;T;T;.;.;.;.
Sift4G	Benign	0.23	T;T;T;.;T;T;T
Polyphen		0.048	B;B;B;B;.;B;B
Vest4		0.47
MutPred		0.69		.;.;Gain of disorder (P = 0.1336);.;.;.;Gain of disorder (P = 0.1336);
MVP		0.69
MPC		0.55
ClinPred		0.20	T
GERP RS		3.0
Varity_R		0.33
gMVP		0.64
Mutation Taster		=53/47	polymorphism

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: rs727505251; hg19: chr19-50735308;