19-50210370-C-A

Variant names:

• chr19-50210370-C-A
• rs750407725
• NM_001145809.2:c.5C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001145809.2(MYH14):​c.5C>A​(p.Ala2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity MYH14_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.5C>A	p.Ala2Glu	missense_variant	Exon 2 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.5C>A	p.Ala2Glu	missense_variant	Exon 2 of 42		NP_001070654.1
MYH14	NM_024729.4	c.5C>A	p.Ala2Glu	missense_variant	Exon 2 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.5C>A	p.Ala2Glu	missense_variant	Exon 2 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434928 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712670

African (AFR) AF: 0.00 AC: 0 AN: 31052

American (AMR) AF: 0.00 AC: 0 AN: 42468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25398

East Asian (EAS) AF: 0.00 AC: 0 AN: 37628

South Asian (SAS) AF: 0.00 AC: 0 AN: 82850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100236

Other (OTH) AF: 0.00 AC: 0 AN: 59038

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 27, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;.;T;.;T;.;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.72	.;T;T;.;T;T;T;.
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.4	L;L;L;L;.;L;.;L
PhyloP100		1.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.53	.;N;N;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;D;.;D
Polyphen		0.78	P;P;P;P;.;P;.;P
Vest4		0.49
MutPred		0.27		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.41
MPC		1.5
ClinPred		0.86	D
GERP RS		4.5
PromoterAI		-0.051	Neutral
Varity_R		0.16
gMVP		0.60
Mutation Taster		=88/12	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: rs750407725; hg19: chr19-50713627;