Variant chr11-2168572-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000360.4(TH):c.406G>C(p.Val136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,688 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.22

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3416894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TH	NM_000360.4 linkuse as main transcript	c.406G>C	p.Val136Leu	missense_variant	3/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3 linkuse as main transcript	c.499G>C	p.Val167Leu	missense_variant	4/14		NP_954986.2
TH	NM_199293.3 linkuse as main transcript	c.487G>C	p.Val163Leu	missense_variant	4/14		NP_954987.2
TH	XM_011520335.3 linkuse as main transcript	c.418G>C	p.Val140Leu	missense_variant	3/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8 linkuse as main transcript	c.406G>C	p.Val136Leu	missense_variant	3/13	1	NM_000360.4	ENSP00000325951	P1	P07101-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459550

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.35

T;.;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.67

T;T;T;T

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.34

T;T;T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.7

L;.;.;.

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.65

N;N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.35

T;T;T;T

Sift4G

Benign

0.72

T;T;T;T

Polyphen

0.0060

B;B;.;B

Vest4

0.34

MutPred

0.42

Loss of helix (P = 0.079);.;.;.;

MVP

0.87

MPC

0.047

ClinPred

0.20

GERP RS

2.4

Varity_R

0.053

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over