rs148235227

Positions:

chr11-2170739-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The ENST00000381178.5(TH):c.134C>T(p.Pro45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,600,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P45P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

TH
ENST00000381178.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -0.969

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047463566).

BP6

Variant 11-2170739-G-A is Benign according to our data. Variant chr11-2170739-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567057.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr11-2170739-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TH	NM_000360.4 linkuse as main transcript	c.91-868C>T		intron_variant		ENST00000352909.8	NP_000351.2
TH	NM_199292.3 linkuse as main transcript	c.134C>T	p.Pro45Leu	missense_variant	2/14		NP_954986.2
TH	NM_199293.3 linkuse as main transcript	c.122C>T	p.Pro41Leu	missense_variant	2/14		NP_954987.2
TH	XM_011520335.3 linkuse as main transcript	c.103-868C>T		intron_variant			XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8 linkuse as main transcript	c.91-868C>T		intron_variant		1	NM_000360.4	ENSP00000325951	P1	P07101-3

Frequencies

GnomAD3 genomes

AF:

0.000113

AC:

AN:

150710

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

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:

0.000237

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000152

AC:

AN:

223280

Hom.:

AF XY:

0.000180

AC XY:

AN XY:

122020

show subpopulations

Gnomad AFR exome

AF:

0.0000739

Gnomad AMR exome

AF:

0.0000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000122

Gnomad NFE exome

AF:

0.000289

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000272

AC:

394

AN:

1449530

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

195

AN XY:

720160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000458

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.0000616

Gnomad4 NFE exome

AF:

0.000341

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000113

AC:

AN:

150826

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

73688

show subpopulations

Gnomad4 AFR

AF:

0.0000243

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:

0.000237

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000277

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 28, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 45 of the TH protein (p.Pro45Leu). This variant is present in population databases (rs148235227, gnomAD 0.03%). 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: 567057). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TH protein function. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.32

CADD

Benign

6.0

DANN

Benign

0.29

DEOGEN2

Benign

0.25

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.48

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.047

T;T

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.020

N;N

REVEL

Benign

0.24

Sift

Uncertain

0.0060

D;D

Sift4G

Benign

0.34

T;T

Polyphen

0.47

P;B

Vest4

0.12

MVP

0.57

MPC

0.046

ClinPred

0.029

GERP RS

-1.7

Varity_R

0.048

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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