11-2171857-G-T

Variant names:

• chr11-2171857-G-T
• rs549435434
• ENST00000853117.1:c.-71C>A

Variant summary

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

The ENST00000853117.1(TH):​c.-71C>A variant causes a 5 prime UTR change. The variant was absent in control chromosomes in GnomAD project. 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: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TH ENST00000853117.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.88
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• tyrosine hydroxylase deficiency

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

ENSG00000295384 (HGNC:):

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=-0.18).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000853117.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.-71C>A		upstream_gene	N/A	NP_000351.2	P07101-3
	TH	NM_199292.3		c.-71C>A		upstream_gene	N/A	NP_954986.2	P07101-1
	TH	NM_199293.3		c.-71C>A		upstream_gene	N/A	NP_954987.2	P07101-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000853117.1		c.-71C>A		5_prime_UTR	Exon 1 of 13	ENSP00000523176.1
	ENSG00000295384	ENST00000729705.1		n.321-2128G>T		intron	N/A
	ENSG00000295384	ENST00000729706.1		n.372-933G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.63e-7 AC: 1 AN: 1309934 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 651470

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30790

American (AMR) AF: 0.00 AC: 0 AN: 40408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24452

East Asian (EAS) AF: 0.00 AC: 0 AN: 37922

South Asian (SAS) AF: 0.00 AC: 0 AN: 80824

European-Finnish (FIN) AF: 0.0000255 AC: 1 AN: 39258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5370

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 995806

Other (OTH) AF: 0.00 AC: 0 AN: 55104

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.93
PhyloP100		3.9
PromoterAI		-0.33	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: rs549435434; hg19: chr11-2193087;