19-50278171-G-A

Variant names:

• chr19-50278171-G-A
• rs876657873
• NM_001145809.2:c.3914G>A

Variant summary

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

The NM_001145809.2(MYH14):​c.3914G>A​(p.Arg1305His) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,310 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. R1305C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	NM_001145809.2	MANE Select	c.3914G>A	p.Arg1305His	missense	Exon 30 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.3815G>A	p.Arg1272His	missense	Exon 29 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.3791G>A	p.Arg1264His	missense	Exon 28 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.3914G>A	p.Arg1305His	missense	Exon 30 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000425460.6	TSL:5	c.3815G>A	p.Arg1272His	missense	Exon 29 of 42	ENSP00000407879.1	Q7Z406-6
	MYH14	ENST00000598205.5	TSL:5	c.3815G>A	p.Arg1272His	missense	Exon 29 of 42	ENSP00000472543.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460618 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726476

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111408

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152310 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.24
MutPred		0.59		Loss of MoRF binding (P = 0.0268)
MVP		0.79
MPC		0.65
ClinPred		0.96	D
GERP RS		3.8
Varity_R		0.056
gMVP		0.29
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs876657873; hg19: chr19-50781428;