11-2164265-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000360.4(TH):c.1462A>G(p.Thr488Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T488T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.107

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=0.3435854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TH	NM_000360.4	c.1462A>G	p.Thr488Ala	missense_variant	13/13	ENST00000352909.8
TH	NM_199292.3	c.1555A>G	p.Thr519Ala	missense_variant	14/14
TH	NM_199293.3	c.1543A>G	p.Thr515Ala	missense_variant	14/14
TH	XM_011520335.3	c.1474A>G	p.Thr492Ala	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8	c.1462A>G	p.Thr488Ala	missense_variant	13/13	1	NM_000360.4	P1
TH	ENST00000381178.5	c.1555A>G	p.Thr519Ala	missense_variant	14/14	1
TH	ENST00000381175.5	c.1543A>G	p.Thr515Ala	missense_variant	14/14	1
TH	ENST00000333684.9	c.1180A>G	p.Thr394Ala	missense_variant	11/11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1340978 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 657042

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Revvity Omics, Revvity

Mar 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	8.1
Dann	Benign	0.68
DEOGEN2	Uncertain	0.74	D;.;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.57	T;T;T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	0.84	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N;N;.;N
REVEL	Benign	0.25
Sift	Benign	0.59	T;T;.;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.019
MutPred		0.49		Gain of disorder (P = 0.1969);.;.;.;
MVP		0.88
MPC		0.57
ClinPred		0.022	T
GERP RS		0.48
Varity_R		0.17
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2185495;