chr11-2168488-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000360.4(TH):c.487+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00992 in 1,612,286 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 10 hom., cov: 32)

Exomes 𝑓: 0.010 ( 114 hom. )

Consequence

TH
NM_000360.4 splice_region, intron

Scores

Splicing: ADA: 0.0005839

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.98

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 11-2168488-C-T is Benign according to our data. Variant chr11-2168488-C-T is described in ClinVar as [Benign]. Clinvar id is 242254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2168488-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00809 (1232/152268) while in subpopulation SAS AF= 0.0126 (61/4824). AF 95% confidence interval is 0.0101. There are 10 homozygotes in gnomad4. There are 633 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4 link	c.487+3G>A	splice_region_variant, intron_variant	Intron 3 of 12	ENST00000352909.8	NP_000351.2	P07101-3
TH	NM_199292.3 link	c.580+3G>A	splice_region_variant, intron_variant	Intron 4 of 13		NP_954986.2	P07101-1P78428
TH	NM_199293.3 link	c.568+3G>A	splice_region_variant, intron_variant	Intron 4 of 13		NP_954987.2	P07101-2P78428
TH	XM_011520335.3 link	c.499+3G>A	splice_region_variant, intron_variant	Intron 3 of 12		XP_011518637.1	P07101-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8 link	c.487+3G>A		splice_region_variant, intron_variant	Intron 3 of 12	1	NM_000360.4	ENSP00000325951.4		P07101-3

Frequencies

GnomAD3 genomes

AF:

0.00809

AC:

1231

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00946

AC:

2298

AN:

242896

Hom.:

AF XY:

0.00974

AC XY:

1295

AN XY:

133018

show subpopulations

Gnomad AFR exome

AF:

0.00153

Gnomad AMR exome

AF:

0.00732

Gnomad ASJ exome

AF:

0.0180

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0106

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0101

AC:

14762

AN:

1460018

Hom.:

114

Cov.:

AF XY:

0.0102

AC XY:

7441

AN XY:

726344

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.00736

Gnomad4 ASJ exome

AF:

0.0184

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0116

Gnomad4 FIN exome

AF:

0.0118

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.00976

GnomAD4 genome

AF:

0.00809

AC:

1232

AN:

152268

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

633

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00216

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.0187

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0126

Gnomad4 FIN

AF:

0.0110

Gnomad4 NFE

AF:

0.0105

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00980

Hom.:

Bravo

AF:

0.00777

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0122

EpiControl

AF:

0.0113

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TH: BP4, BS1, BS2 -

Autosomal recessive DOPA responsive dystonia

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:1

Aug 10, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TH-related disorder

Benign:1

Apr 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00058

dbscSNV1_RF

Benign

0.0080

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over