11-2164237-C-A

Position:

• chr11-2164237-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41566506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.1490G>T	p.Gly497Val	missense_variant	13/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1583G>T	p.Gly528Val	missense_variant	14/14		NP_954986.2
TH	NM_199293.3	c.1571G>T	p.Gly524Val	missense_variant	14/14		NP_954987.2
TH	XM_011520335.3	c.1502G>T	p.Gly501Val	missense_variant	13/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1490G>T	p.Gly497Val	missense_variant	13/13	1	NM_000360.4	ENSP00000325951.4
TH	ENST00000381178.5	c.1583G>T	p.Gly528Val	missense_variant	14/14	1		ENSP00000370571.1
TH	ENST00000381175.5	c.1571G>T	p.Gly524Val	missense_variant	14/14	1		ENSP00000370567.1
TH	ENST00000333684.9	c.1208G>T	p.Gly403Val	missense_variant	11/11	1		ENSP00000328814.6

Frequencies

GnomAD3 genomes Cov.: 33

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.67e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000333 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000833 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 528 of the TH protein (p.Gly528Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TH-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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;T;T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N;N;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.047	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.91	P;P;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs753632777; hg19: chr11-2185467;