rs10840489

Positions:

• chr11-2171568-C-T

Variant summary

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

The ENST00000352909.8(TH):​c.90+129G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 980,520 control chromosomes in the GnomAD database, including 11,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1637 hom., cov: 31)
  • Exomes 𝑓: 0.15 (9425 hom.)
• Consequence: TH ENST00000352909.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.13

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=-0.98).
• BP6: Variant 11-2171568-C-T is Benign according to our data. Variant chr11-2171568-C-T is described in ClinVar as [Benign]. Clinvar id is 1258844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.90+129G>A		intron_variant		ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.102+117G>A		intron_variant			NP_954986.2
TH	NM_199293.3	c.90+129G>A		intron_variant			NP_954987.2
TH	XM_011520335.3	c.102+117G>A		intron_variant			XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.90+129G>A		intron_variant		1	NM_000360.4	ENSP00000325951	P1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21884 AN: 151864 Hom.: 1628 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.145 AC: 120191 AN: 828538 Hom.: 9425 AF XY: 0.145 AC XY: 62084 AN XY: 428832

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.144 AC: 21925 AN: 151982 Hom.: 1637 Cov.: 31 AF XY: 0.146 AC XY: 10844 AN XY: 74286

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.135

Alfa AF: 0.141 Hom.: 1625

Bravo AF: 0.147

Asia WGS AF: 0.124 AC: 434 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
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	-0.98
CADD	Benign	0.37
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs10840489; hg19: chr11-2192798;