11-2166625-G-C

Position:

• chr11-2166625-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000360.4(TH):​c.977+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,578,486 control chromosomes in the GnomAD database, including 91,703 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 0.27 (6578 hom., cov: 35)
  • Exomes 𝑓: 0.34 (85125 hom.)
• Consequence: TH NM_000360.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001468
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0860

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=-0.74).
• BP6: Variant 11-2166625-G-C is Benign according to our data. Variant chr11-2166625-G-C is described in ClinVar as [Benign]. Clinvar id is 263250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2166625-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TH	NM_000360.4	c.977+8C>G		splice_region_variant, intron_variant		ENST00000352909.8
TH	NM_199292.3	c.1070+8C>G		splice_region_variant, intron_variant
TH	NM_199293.3	c.1058+8C>G		splice_region_variant, intron_variant
TH	XM_011520335.3	c.989+8C>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8	c.977+8C>G		splice_region_variant, intron_variant		1	NM_000360.4	P1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41314 AN: 152114 Hom.: 6578 Cov.: 35

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.279 AC: 50436 AN: 180986 Hom.: 8120 AF XY: 0.278 AC XY: 27547 AN XY: 98990

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.0376

Gnomad SAS exome AF: 0.166

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.335 AC: 478037 AN: 1426256 Hom.: 85125 Cov.: 78 AF XY: 0.331 AC XY: 233704 AN XY: 706218

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.236

Gnomad4 ASJ exome AF: 0.363

Gnomad4 EAS exome AF: 0.0361

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.369

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.271 AC: 41307 AN: 152230 Hom.: 6578 Cov.: 35 AF XY: 0.265 AC XY: 19748 AN XY: 74434

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.363

Gnomad4 EAS AF: 0.0432

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.260

Alfa AF: 0.306 Hom.: 2477

Bravo AF: 0.260

Asia WGS AF: 0.115 AC: 401 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Benign:6

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 39. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.3
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs12419447; hg19: chr11-2187855; COSMIC: COSV60767439; COSMIC: COSV60767439;