Genetic Variant NM_000360.4:c.1382C>G (chr11-2164345-G-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000360.4(TH):c.1382C>G(p.Pro461Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P461L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 6.70

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

TH-deficient dopa-responsive dystonia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
tyrosine hydroxylase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen

TH links:

ENSG00000295384 (HGNC:):

ENSG00000295384 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000360.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2164345-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1004173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000360.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TH	NM_000360.4	MANE Select	c.1382C>G	p.Pro461Arg	missense	Exon 13 of 13	NP_000351.2	P07101-3
TH	NM_199292.3		c.1475C>G	p.Pro492Arg	missense	Exon 14 of 14	NP_954986.2	P07101-1
TH	NM_199293.3		c.1463C>G	p.Pro488Arg	missense	Exon 14 of 14	NP_954987.2	P07101-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TH	ENST00000352909.8	TSL:1 MANE Select	c.1382C>G	p.Pro461Arg	missense	Exon 13 of 13	ENSP00000325951.4	P07101-3
TH	ENST00000381178.5	TSL:1	c.1475C>G	p.Pro492Arg	missense	Exon 14 of 14	ENSP00000370571.1	P07101-1
TH	ENST00000381175.5	TSL:1	c.1463C>G	p.Pro488Arg	missense	Exon 14 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1394104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687790

African (AFR)

AF:

0.00

AC:

AN:

30446

American (AMR)

AF:

0.00

AC:

AN:

37024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23156

East Asian (EAS)

AF:

0.00

AC:

AN:

36390

South Asian (SAS)

AF:

0.00

AC:

AN:

78270

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075274

Other (OTH)

AF:

0.00

AC:

AN:

57388

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive DOPA responsive dystonia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

PhyloP100

6.7

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-8.1

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MutPred

0.85

Gain of MoRF binding (P = 0.0075)

MVP

0.99

MPC

1.6

ClinPred

1.0

GERP RS

3.4

Varity_R

0.86

gMVP

0.86

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over