rs727503225

Variant names:

• chr19-50280352-C-A
• rs727503225
• NM_001145809.2:c.4259C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50280352-C-A
• chr19-50280352-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145809.2(MYH14):​c.4259C>A​(p.Ala1420Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,394,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. A1420V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30478436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.4259C>A	p.Ala1420Glu	missense_variant	Exon 32 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.4160C>A	p.Ala1387Glu	missense_variant	Exon 31 of 42		NP_001070654.1
MYH14	NM_024729.4	c.4136C>A	p.Ala1379Glu	missense_variant	Exon 30 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.4259C>A	p.Ala1420Glu	missense_variant	Exon 32 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1394786 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 687546

African (AFR) AF: 0.00 AC: 0 AN: 31502

American (AMR) AF: 0.00 AC: 0 AN: 35552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25034

East Asian (EAS) AF: 0.00 AC: 0 AN: 35678

South Asian (SAS) AF: 0.00 AC: 0 AN: 78848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4208

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1077252

Other (OTH) AF: 0.00 AC: 0 AN: 57666

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;.;.;T;.;.;T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.77	.;T;T;T;.;T;.;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.0	.;.;.;L;.;.;L;.
PhyloP100		0.17
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.0	.;.;N;.;.;.;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;T;D;D;.;D;D;T
Polyphen		0.97	D;.;D;D;D;D;D;.
Vest4		0.27
MVP		0.42
MPC		0.43
ClinPred		0.93	D
GERP RS		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.089
gMVP		0.56
Mutation Taster		=94/6	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: rs727503225; hg19: chr19-50783609;