11-2169361-C-G

Position:

• chr11-2169361-C-G

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.312+289G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 152,058 control chromosomes in the GnomAD database, including 3,379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.19 (3379 hom., cov: 33)
• Consequence: TH NM_000360.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.205

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=-0.83).
• BP6: Variant 11-2169361-C-G is Benign according to our data. Variant chr11-2169361-C-G is described in ClinVar as [Benign]. Clinvar id is 526231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TH	NM_000360.4	c.312+289G>C		intron_variant		ENST00000352909.8
TH	NM_199292.3	c.405+289G>C		intron_variant
TH	NM_199293.3	c.393+289G>C		intron_variant
TH	XM_011520335.3	c.324+289G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8	c.312+289G>C		intron_variant		1	NM_000360.4	P1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28759 AN: 151940 Hom.: 3379 Cov.: 33

Gnomad AFR AF: 0.0691

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.235

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.189 AC: 28752 AN: 152058 Hom.: 3379 Cov.: 33 AF XY: 0.195 AC XY: 14479 AN XY: 74302

Gnomad4 AFR AF: 0.0689

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.470

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.238

Alfa AF: 0.197 Hom.: 438

Bravo AF: 0.179

Asia WGS AF: 0.423 AC: 1472 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2018

- -

Autosomal recessive DOPA responsive dystonia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.76

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: rs7482510; hg19: chr11-2190591; COSMIC: COSV60768290; COSMIC: COSV60768290;