chr11-2168488-C-T

Variant names:

• chr11-2168488-C-T
• rs11042950
• NM_000360.4:c.487+3G>A

Variant summary

Our verdict is Benign. The variant received -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 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

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

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

Ensembl

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

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

GnomAD2 exomes AF: 0.00946 AC: 2298 AN: 242896 AF XY: 0.00974

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 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 AC: 44 AN: 33464

Gnomad4 AMR exome AF: 0.00736 AC: 329 AN: 44702

Gnomad4 ASJ exome AF: 0.0184 AC: 481 AN: 26112

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39686

Gnomad4 SAS exome AF: 0.0116 AC: 1002 AN: 86218

Gnomad4 FIN exome AF: 0.0118 AC: 614 AN: 52022

Gnomad4 NFE exome AF: 0.0104 AC: 11608 AN: 1111808

Gnomad4 Remaining exome AF: 0.00976 AC: 589 AN: 60322

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 AC: 0.00216429 AN: 0.00216429

Gnomad4 AMR AF: 0.0109 AC: 0.0108511 AN: 0.0108511

Gnomad4 ASJ AF: 0.0187 AC: 0.0187428 AN: 0.0187428

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.0126 AC: 0.0126451 AN: 0.0126451

Gnomad4 FIN AF: 0.0110 AC: 0.011019 AN: 0.011019

Gnomad4 NFE AF: 0.0105 AC: 0.010485 AN: 0.010485

Gnomad4 OTH AF: 0.00851 AC: 0.00851466 AN: 0.00851466

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

-

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. -

Jun 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

- -

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	17
DANN	Benign	0.77
Mutation Taster		=57/43	polymorphism

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;