rs538345855

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000360.4(TH):c.313-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000877 in 1,352,854 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00091 ( 13 hom. )

Consequence

TH
NM_000360.4 intron

Scores

Splicing: ADA: 0.00003605

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.105

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: 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 11-2168674-G-A is Benign according to our data. Variant chr11-2168674-G-A is described in ClinVar as Benign. ClinVar VariationId is 304082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000527 (70/132842) while in subpopulation SAS AF = 0.0168 (66/3936). AF 95% confidence interval is 0.0135. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4 link	c.313-9C>T		intron_variant	Intron 2 of 12	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.313-9C>T		intron_variant	Intron 2 of 12	1	NM_000360.4	ENSP00000325951.4		P07101-3

Frequencies

GnomAD3 genomes

AF:

0.000527

AC:

AN:

132766

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000156

Gnomad OTH

AF:

0.000532

GnomAD2 exomes

AF:

0.00161

AC:

381

AN:

236764

AF XY:

0.00216

show subpopulations

Gnomad AFR exome

AF:

0.0000717

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000287

Gnomad OTH exome

AF:

0.000863

GnomAD4 exome

AF:

0.000915

AC:

1116

AN:

1220012

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

776

AN XY:

604544

show subpopulations

African (AFR)

AF:

0.000113

AC:

AN:

26476

American (AMR)

AF:

0.00

AC:

AN:

37518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17098

East Asian (EAS)

AF:

0.00

AC:

AN:

17446

South Asian (SAS)

AF:

0.0116

AC:

973

AN:

83718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31592

Middle Eastern (MID)

AF:

0.000719

AC:

AN:

4170

European-Non Finnish (NFE)

AF:

0.0000752

AC:

AN:

957608

Other (OTH)

AF:

0.00146

AC:

AN:

44386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000527

AC:

AN:

132842

Hom.:

Cov.:

AF XY:

0.000890

AC XY:

AN XY:

62916

show subpopulations

African (AFR)

AF:

0.0000553

AC:

AN:

36134

American (AMR)

AF:

0.00

AC:

AN:

11216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3338

East Asian (EAS)

AF:

0.00

AC:

AN:

3954

South Asian (SAS)

AF:

0.0168

AC:

AN:

3936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.0000156

AC:

AN:

64170

Other (OTH)

AF:

0.000527

AC:

AN:

1896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.000117

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Benign:3

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Apr 12, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.1

(source)

DANN

Benign

0.88

PhyloP100

0.10

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000036

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over