rs2070762

Positions:

• chr11-2165105-A-G
• chr11-2165105-A-T

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.1334+127T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,423,550 control chromosomes in the GnomAD database, including 174,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15328 hom., cov: 33)
  • Exomes 𝑓: 0.50 (158957 hom.)
• Consequence: TH NM_000360.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.607

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=-0.88).
• BP6: Variant 11-2165105-A-G is Benign according to our data. Variant chr11-2165105-A-G is described in ClinVar as [Benign]. Clinvar id is 1164243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.1334+127T>C		intron_variant		ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1427+127T>C		intron_variant			NP_954986.2
TH	NM_199293.3	c.1415+127T>C		intron_variant			NP_954987.2
TH	XM_011520335.3	c.1346+127T>C		intron_variant			XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1334+127T>C		intron_variant		1	NM_000360.4	ENSP00000325951	P1
TH	ENST00000333684.9	c.1052+127T>C		intron_variant		1		ENSP00000328814
TH	ENST00000381175.5	c.1415+127T>C		intron_variant		1		ENSP00000370567
TH	ENST00000381178.5	c.1427+127T>C		intron_variant		1		ENSP00000370571

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65450 AN: 151896 Hom.: 15314 Cov.: 33

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.474

GnomAD4 exome AF: 0.496 AC: 630422 AN: 1271536 Hom.: 158957 AF XY: 0.496 AC XY: 316625 AN XY: 638710

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.652

Gnomad4 ASJ exome AF: 0.457

Gnomad4 EAS exome AF: 0.474

Gnomad4 SAS exome AF: 0.504

Gnomad4 FIN exome AF: 0.498

Gnomad4 NFE exome AF: 0.499

Gnomad4 OTH exome AF: 0.476

GnomAD4 genome AF: 0.431 AC: 65494 AN: 152014 Hom.: 15328 Cov.: 33 AF XY: 0.435 AC XY: 32321 AN XY: 74300

Gnomad4 AFR AF: 0.240

Gnomad4 AMR AF: 0.576

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.438

Gnomad4 SAS AF: 0.504

Gnomad4 FIN AF: 0.483

Gnomad4 NFE AF: 0.497

Gnomad4 OTH AF: 0.478

Alfa AF: 0.487 Hom.: 23097

Bravo AF: 0.427

Asia WGS AF: 0.468 AC: 1626 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 18208403) -

Autosomal recessive DOPA responsive dystonia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.4
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2070762; hg19: chr11-2186335; COSMIC: COSV51747073; COSMIC: COSV51747073;