rs11042950

Positions:

• chr11-2168488-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000360.4(TH):​c.487+3G>A variant causes a splice donor 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. 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_donor_region, intron
• Scores: Splicing: ADA: 0.0005839
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.98

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]

ACMG classification

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	HGVSp	Effect	#exon/exons	MANE	UniProt
TH	NM_000360.4	c.487+3G>A		splice_donor_region_variant, intron_variant		ENST00000352909.8
TH	NM_199292.3	c.580+3G>A		splice_donor_region_variant, intron_variant
TH	NM_199293.3	c.568+3G>A		splice_donor_region_variant, intron_variant
TH	XM_011520335.3	c.499+3G>A		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8	c.487+3G>A		splice_donor_region_variant, intron_variant		1	NM_000360.4	P1

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 1231 AN: 152150 Hom.: 10 Cov.: 32

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.: 23 AF XY: 0.00974 AC XY: 1295 AN XY: 133018

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.: 34 AF XY: 0.0102 AC XY: 7441 AN XY: 726344

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.: 10 Cov.: 32 AF XY: 0.00850 AC XY: 633 AN XY: 74440

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.: 4

Bravo AF: 0.00777

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0122

EpiControl AF: 0.0113

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TH: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2018	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. -

Autosomal recessive DOPA responsive dystonia Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

TH-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2023

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). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
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

Other links and lift over

dbSNP: rs11042950; hg19: chr11-2189718;