NM_000360.4:c.1490G>T

Variant names:

• chr11-2164237-C-A
• rs753632777
• NM_000360.4:c.1490G>T

Variant summary

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

The NM_000360.4(TH):​c.1490G>T​(p.Gly497Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,308,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. G497D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88
• Publications: 1 publications found

Genes affected

TH (HGNC:11782): (tyrosine hydroxylase) The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

TH Gene-Disease associations (from GenCC):

• TH-deficient dopa-responsive dystonia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• tyrosine hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen

ENSG00000295384 (HGNC:):

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=0.41566506).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000360.4. 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
	TH	NM_000360.4	MANE Select	c.1490G>T	p.Gly497Val	missense	Exon 13 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.1583G>T	p.Gly528Val	missense	Exon 14 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.1571G>T	p.Gly524Val	missense	Exon 14 of 14	NP_954987.2	P07101-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.1490G>T	p.Gly497Val	missense	Exon 13 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.1583G>T	p.Gly528Val	missense	Exon 14 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.1571G>T	p.Gly524Val	missense	Exon 14 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 145726 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.64e-7 AC: 1 AN: 1308738 Hom.: 0 Cov.: 31 AF XY: 0.00000156 AC XY: 1 AN XY: 639056

African (AFR) AF: 0.00 AC: 0 AN: 27278

American (AMR) AF: 0.00 AC: 0 AN: 25648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19098

East Asian (EAS) AF: 0.00 AC: 0 AN: 33950

South Asian (SAS) AF: 0.00 AC: 0 AN: 63000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4844

European-Non Finnish (NFE) AF: 9.67e-7 AC: 1 AN: 1034282

Other (OTH) AF: 0.00 AC: 0 AN: 53410

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000333 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000833 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive DOPA responsive dystonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.42	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.43
Sift	Benign	0.047	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.15
MVP		0.84
MPC		1.0
ClinPred		0.91	D
GERP RS		4.2
Varity_R		0.37
gMVP		0.50
Mutation Taster		=83/17	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: rs753632777; hg19: chr11-2185467;