Genetic Variant NM_000360.4:c.1475C>A (chr11-2164252-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000360.4(TH):c.1475C>A(p.Ala492Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,329,660 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A492V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.58

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

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.1475C>A	p.Ala492Glu	missense	Exon 13 of 13	NP_000351.2	P07101-3
TH	NM_199292.3		c.1568C>A	p.Ala523Glu	missense	Exon 14 of 14	NP_954986.2	P07101-1
TH	NM_199293.3		c.1556C>A	p.Ala519Glu	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.1475C>A	p.Ala492Glu	missense	Exon 13 of 13	ENSP00000325951.4	P07101-3
TH	ENST00000381178.5	TSL:1	c.1568C>A	p.Ala523Glu	missense	Exon 14 of 14	ENSP00000370571.1	P07101-1
TH	ENST00000381175.5	TSL:1	c.1556C>A	p.Ala519Glu	missense	Exon 14 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1329660

Hom.:

Cov.:

AF XY:

0.00000307

AC XY:

AN XY:

650812

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28058

American (AMR)

AF:

0.00

AC:

AN:

27546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19730

East Asian (EAS)

AF:

0.0000572

AC:

AN:

34972

South Asian (SAS)

AF:

0.00

AC:

AN:

66688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5064

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1044952

Other (OTH)

AF:

0.00

AC:

AN:

54456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.6

PhyloP100

7.6

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.59

MutPred

0.77

Gain of disorder (P = 0.0303)

MVP

0.99

MPC

1.7

ClinPred

1.0

GERP RS

4.3

Varity_R

0.91

gMVP

0.93

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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