chr19-50268173-C-G

Variant names:

• chr19-50268173-C-G
• rs757658628
• NM_001145809.2:c.2839C>G

Variant summary

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

The NM_001145809.2(MYH14):​c.2839C>G​(p.Arg947Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,393,990 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R947C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	NM_001145809.2	MANE Select	c.2839C>G	p.Arg947Gly	missense	Exon 24 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.2740C>G	p.Arg914Gly	missense	Exon 23 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.2716C>G	p.Arg906Gly	missense	Exon 22 of 41	NP_079005.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.2839C>G	p.Arg947Gly	missense	Exon 24 of 43	ENSP00000493594.1
	MYH14	ENST00000599920.5	TSL:1	c.2740C>G	p.Arg914Gly	missense	Exon 23 of 24	ENSP00000469573.1
	MYH14	ENST00000425460.6	TSL:5	c.2740C>G	p.Arg914Gly	missense	Exon 23 of 42	ENSP00000407879.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1393990 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 687576

African (AFR) AF: 0.00 AC: 0 AN: 31568

American (AMR) AF: 0.00 AC: 0 AN: 35774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35774

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4520

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078786

Other (OTH) AF: 0.00 AC: 0 AN: 57866

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.87	P
Vest4		0.34
MutPred		0.53		Loss of MoRF binding (P = 0.0806)
MVP		0.68
MPC		1.1
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.24
gMVP		0.46
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757658628; hg19: chr19-50771430;