chr11-2169361-C-G

Variant names:

• chr11-2169361-C-G
• rs7482510
• NM_000360.4:c.312+289G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

TH Gene-Disease associations (from GenCC):

• TH-deficient dopa-responsive dystonia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• tyrosine hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000360.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.312+289G>C		intron	N/A	NP_000351.2
	TH	NM_199292.3		c.405+289G>C		intron	N/A	NP_954986.2
	TH	NM_199293.3		c.393+289G>C		intron	N/A	NP_954987.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.312+289G>C		intron	N/A	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.405+289G>C		intron	N/A	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.393+289G>C		intron	N/A	ENSP00000370567.1

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

African (AFR) AF: 0.0689 AC: 2861 AN: 41498

American (AMR) AF: 0.173 AC: 2642 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1103 AN: 3472

East Asian (EAS) AF: 0.470 AC: 2423 AN: 5150

South Asian (SAS) AF: 0.392 AC: 1887 AN: 4818

European-Finnish (FIN) AF: 0.222 AC: 2349 AN: 10584

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14789 AN: 67938

Other (OTH) AF: 0.238 AC: 501 AN: 2106

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

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive DOPA responsive dystonia Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.76
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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