11-2164237-C-T

Position:

chr11-2164237-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000360.4(TH):c.1490G>A(p.Gly497Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,946 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: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1355035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4 linkuse as main transcript	c.1490G>A	p.Gly497Asp	missense_variant	13/13	ENST00000352909.8	NP_000351.2	P07101-3
TH	NM_199292.3 linkuse as main transcript	c.1583G>A	p.Gly528Asp	missense_variant	14/14		NP_954986.2	P07101-1P78428
TH	NM_199293.3 linkuse as main transcript	c.1571G>A	p.Gly524Asp	missense_variant	14/14		NP_954987.2	P07101-2P78428
TH	XM_011520335.3 linkuse as main transcript	c.1502G>A	p.Gly501Asp	missense_variant	13/13		XP_011518637.1	P07101-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TH	ENST00000352909.8 linkuse as main transcript	c.1490G>A	p.Gly497Asp	missense_variant	13/13	1	NM_000360.4	ENSP00000325951.4	P07101-3
TH	ENST00000381178.5 linkuse as main transcript	c.1583G>A	p.Gly528Asp	missense_variant	14/14	1		ENSP00000370571.1	P07101-1
TH	ENST00000381175.5 linkuse as main transcript	c.1571G>A	p.Gly524Asp	missense_variant	14/14	1		ENSP00000370567.1	P07101-2
TH	ENST00000333684.9 linkuse as main transcript	c.1208G>A	p.Gly403Asp	missense_variant	11/11	1		ENSP00000328814.6	P07101-6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

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

GnomAD3 exomes

AF:

0.0000618

AC:

AN:

145726

Hom.:

AF XY:

0.0000635

AC XY:

AN XY:

78742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000716

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000341

GnomAD4 exome

AF:

0.00000688

AC:

AN:

1308738

Hom.:

Cov.:

AF XY:

0.00000782

AC XY:

AN XY:

639056

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000147

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000749

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000583

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 528 of the TH protein (p.Gly528Asp). This variant is present in population databases (rs753632777, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with TH-related conditions. ClinVar contains an entry for this variant (Variation ID: 936679). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.;.;.

Eigen

Benign

0.062

Eigen_PC

Benign

0.078

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

1.4

L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.39

N;N;.;N

REVEL

Uncertain

0.40

Sift

Benign

0.17

T;T;.;T

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.79

P;P;.;B

Vest4

0.15

MutPred

0.27

Gain of solvent accessibility (P = 0.0638);.;.;.;

MVP

0.77

MPC

0.92

ClinPred

0.22

GERP RS

4.2

Varity_R

0.32

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over