ENST00000729705.1:n.321-2130A>G

Variant names:

• chr11-2171855-A-G
• rs1554924394
• ENST00000729705.1:n.321-2130A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000729705.1(ENSG00000295384):​n.321-2130A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,330,116 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ENSG00000295384 ENST00000729705.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.60
• Publications: 0 publications found

Genes affected

ENSG00000295384 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000729705.1. 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.-69T>C		upstream_gene	N/A	NP_000351.2
	TH	NM_199292.3		c.-69T>C		upstream_gene	N/A	NP_954986.2
	TH	NM_199293.3		c.-69T>C		upstream_gene	N/A	NP_954987.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000295384	ENST00000729705.1		n.321-2130A>G		intron	N/A
	ENSG00000295384	ENST00000729706.1		n.372-935A>G		intron	N/A
	TH	ENST00000352909.8	TSL:1 MANE Select	c.-69T>C		upstream_gene	N/A	ENSP00000325951.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1330116 Hom.: 0 Cov.: 19 AF XY: 0.00000302 AC XY: 2 AN XY: 661406

African (AFR) AF: 0.00 AC: 0 AN: 31176

American (AMR) AF: 0.00 AC: 0 AN: 40924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24662

East Asian (EAS) AF: 0.00 AC: 0 AN: 38130

South Asian (SAS) AF: 0.00 AC: 0 AN: 81620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5406

European-Non Finnish (NFE) AF: 0.00000197 AC: 2 AN: 1012698

Other (OTH) AF: 0.00 AC: 0 AN: 55800

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.92
PhyloP100		2.6
PromoterAI		-0.25	Neutral

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: rs1554924394; hg19: chr11-2193085;