dbSNP rs28934580: TH:p.Arg306Leu (chr11-2166693-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000360.4(TH):c.917G>T(p.Arg306Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R306H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.41

Publications

11 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
tyrosine hydroxylase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

TH links:

ENSG00000295384 (HGNC:):

ENSG00000295384 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2166693-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4 link	c.917G>T	p.Arg306Leu	missense_variant	Exon 8 of 13	ENST00000352909.8	NP_000351.2	P07101-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8 link	c.917G>T	p.Arg306Leu	missense_variant	Exon 8 of 13	1	NM_000360.4	ENSP00000325951.4		P07101-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1406608

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694580

African (AFR)

AF:

0.00

AC:

AN:

32310

American (AMR)

AF:

0.00

AC:

AN:

36442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25214

East Asian (EAS)

AF:

0.00

AC:

AN:

36670

South Asian (SAS)

AF:

0.00

AC:

AN:

79946

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083832

Other (OTH)

AF:

0.00

AC:

AN:

58362

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.64

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.8

H;.;.

PhyloP100

7.4

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-6.4

D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.90

MutPred

0.85

Loss of catalytic residue at R337 (P = 0.003);.;.;

MVP

0.98

MPC

1.7

ClinPred

1.0

GERP RS

3.3

Varity_R

0.98

gMVP

0.96

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over