ENST00000853117.1:c.-71C>T – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The ENST00000853117.1(TH):c.-71C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000116 in 1,462,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

TH
ENST00000853117.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.88

Publications

2 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: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-2171857-G-A is Pathogenic according to our data. Variant chr11-2171857-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 558656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.12). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000853117.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TH	NM_000360.4	MANE Select	c.-71C>T	upstream_gene	N/A	NP_000351.2	P07101-3
TH	NM_199292.3		c.-71C>T	upstream_gene	N/A	NP_954986.2	P07101-1
TH	NM_199293.3		c.-71C>T	upstream_gene	N/A	NP_954987.2	P07101-2

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
TH	ENST00000853117.1	c.-71C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	ENSP00000523176.1
TH	ENST00000853117.1	c.-71C>T	5_prime_UTR	Exon 1 of 13	ENSP00000523176.1
ENSG00000295384	ENST00000729705.1	n.321-2128G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000992

AC:

AN:

1309932

Hom.:

Cov.:

AF XY:

0.00000767

AC XY:

AN XY:

651468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30790

American (AMR)

AF:

0.00

AC:

AN:

40408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24452

East Asian (EAS)

AF:

0.0000264

AC:

AN:

37922

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5370

European-Non Finnish (NFE)

AF:

0.0000110

AC:

AN:

995804

Other (OTH)

AF:

0.00

AC:

AN:

55104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41526

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive DOPA responsive dystonia (6)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Benign

0.93

PhyloP100

3.9

PromoterAI

-0.28

Neutral

(source)

Mutation Taster

=121/179

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over