rs76240471

Positions:

• chr11-2169695-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000360.4(TH):​c.267G>A​(p.Arg89=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,613,418 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (165 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.282

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 11-2169695-C-T is Benign according to our data. Variant chr11-2169695-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2169695-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.282 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.267G>A	p.Arg89=	synonymous_variant	2/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.360G>A	p.Arg120=	synonymous_variant	3/14		NP_954986.2
TH	NM_199293.3	c.348G>A	p.Arg116=	synonymous_variant	3/14		NP_954987.2
TH	XM_011520335.3	c.279G>A	p.Arg93=	synonymous_variant	2/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.267G>A	p.Arg89=	synonymous_variant	2/13	1	NM_000360.4	ENSP00000325951	P1

Frequencies

GnomAD3 genomes AF: 0.00526 AC: 800 AN: 152152 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0487

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00947 AC: 2359 AN: 249110 Hom.: 52 AF XY: 0.0114 AC XY: 1545 AN XY: 135038

Gnomad AFR exome AF: 0.000988

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0448

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00483

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.00656 AC: 9580 AN: 1461148 Hom.: 165 Cov.: 32 AF XY: 0.00781 AC XY: 5674 AN XY: 726866

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00519

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0434

Gnomad4 FIN exome AF: 0.000170

Gnomad4 NFE exome AF: 0.00366

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.00527 AC: 803 AN: 152270 Hom.: 16 Cov.: 33 AF XY: 0.00603 AC XY: 449 AN XY: 74458

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0491

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00393

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00566 Hom.: 5

Bravo AF: 0.00504

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00806

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Benign:7

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely 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	Genome-Nilou Lab	Jul 10, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 04, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.4
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs76240471; hg19: chr11-2190925;