Variant 11-2167468-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_ModerateBP6_Moderate

The NM_000360.4(TH):c.662G>A(p.Arg221His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,562,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R221C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.551

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.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000360.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23080409).

BP6

Variant 11-2167468-C-T is Benign according to our data. Variant chr11-2167468-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1461571.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TH	NM_000360.4 linkuse as main transcript	c.662G>A	p.Arg221His	missense_variant	6/13	ENST00000352909.8
TH	NM_199292.3 linkuse as main transcript	c.755G>A	p.Arg252His	missense_variant	7/14
TH	NM_199293.3 linkuse as main transcript	c.743G>A	p.Arg248His	missense_variant	7/14
TH	XM_011520335.3 linkuse as main transcript	c.674G>A	p.Arg225His	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8 linkuse as main transcript	c.662G>A	p.Arg221His	missense_variant	6/13	1	NM_000360.4	P1	P07101-3

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000407

AC:

AN:

171856

Hom.:

AF XY:

0.0000437

AC XY:

AN XY:

91468

show subpopulations

Gnomad AFR exome

AF:

0.000399

Gnomad AMR exome

AF:

0.0000379

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000289

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000191

AC:

AN:

1410630

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

696860

show subpopulations

Gnomad4 AFR exome

AF:

0.000123

Gnomad4 AMR exome

AF:

0.0000268

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:

0.0000175

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000693

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000520

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.82

D;.;.;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.85

T;T;D;T

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.9

L;.;.;.

MutationTaster

Benign

0.97

N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.7

N;N;.;N

REVEL

Uncertain

0.32

Sift

Benign

0.30

T;T;.;T

Sift4G

Benign

0.21

T;T;T;T

Polyphen

0.017

B;B;.;B

Vest4

0.25

MVP

0.89

MPC

0.055

ClinPred

0.027

GERP RS

-0.55

Varity_R

0.19

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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