19-50309669-C-G

Variant names:

• chr19-50309669-C-G
• rs201986144
• NM_001145809.2:c.5990C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001145809.2(MYH14):​c.5990C>G​(p.Thr1997Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,610,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T1997M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 14 AD gene.

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.5990C>G	p.Thr1997Arg	missense	Exon 43 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.5891C>G	p.Thr1964Arg	missense	Exon 42 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.5867C>G	p.Thr1956Arg	missense	Exon 41 of 41	NP_079005.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.5990C>G	p.Thr1997Arg	missense	Exon 43 of 43	ENSP00000493594.1
	MYH14	ENST00000425460.6	TSL:5	c.5891C>G	p.Thr1964Arg	missense	Exon 42 of 42	ENSP00000407879.1
	MYH14	ENST00000598205.5	TSL:5	c.5891C>G	p.Thr1964Arg	missense	Exon 42 of 42	ENSP00000472543.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151854 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000207 AC: 5 AN: 242058 AF XY: 0.0000228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000917

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000960 AC: 14 AN: 1458960 Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 10 AN XY: 725482

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.0000225 AC: 1 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.0000468 AC: 4 AN: 85422

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110888

Other (OTH) AF: 0.0000166 AC: 1 AN: 60270

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151970 Hom.: 0 Cov.: 29 AF XY: 0.0000269 AC XY: 2 AN XY: 74286

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67960

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.35
Sift	Benign	0.51	T
Sift4G	Benign	0.48	T
Polyphen		0.59	P
Vest4		0.36
MutPred		0.18		Loss of phosphorylation at T1956 (P = 0.0196)
MVP		0.87
MPC		0.18
ClinPred		0.088	T
GERP RS		3.8
Varity_R		0.25
gMVP		0.49
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201986144; hg19: chr19-50812926;