11-2169289-A-G

Variant names:

• chr11-2169289-A-G
• rs7483056
• NM_000360.4:c.312+361T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000360.4(TH):​c.312+361T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 151,888 control chromosomes in the GnomAD database, including 17,157 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (17157 hom., cov: 32)
• Consequence: TH NM_000360.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.84
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.561 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+361T>C		intron	N/A	NP_000351.2
	TH	NM_199292.3		c.405+361T>C		intron	N/A	NP_954986.2
	TH	NM_199293.3		c.393+361T>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+361T>C		intron	N/A	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.405+361T>C		intron	N/A	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.393+361T>C		intron	N/A	ENSP00000370567.1

Frequencies

GnomAD3 genomes AF: 0.474 AC: 71901 AN: 151772 Hom.: 17133 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.482

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

GnomAD4 genome AF: 0.474 AC: 71970 AN: 151888 Hom.: 17157 Cov.: 32 AF XY: 0.477 AC XY: 35417 AN XY: 74216

African (AFR) AF: 0.457 AC: 18935 AN: 41400

American (AMR) AF: 0.571 AC: 8724 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1641 AN: 3472

East Asian (EAS) AF: 0.491 AC: 2526 AN: 5142

South Asian (SAS) AF: 0.471 AC: 2271 AN: 4822

European-Finnish (FIN) AF: 0.509 AC: 5375 AN: 10556

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.455 AC: 30903 AN: 67916

Other (OTH) AF: 0.482 AC: 1019 AN: 2112

Alfa AF: 0.458 Hom.: 15751

Bravo AF: 0.477

Asia WGS AF: 0.454 AC: 1575 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.31
DANN	Benign	0.43
PhyloP100		-2.8
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: rs7483056; hg19: chr11-2190519; COSMIC: COSV60767560; COSMIC: COSV60767560;