rs1554923802

Positions:

• chr11-2169649-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000352909.8(TH):​c.312+1G>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TH ENST00000352909.8 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.52

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.14792503 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2169649-C-T is Pathogenic according to our data. Variant chr11-2169649-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.312+1G>A		splice_donor_variant		ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.405+1G>A		splice_donor_variant			NP_954986.2
TH	NM_199293.3	c.393+1G>A		splice_donor_variant			NP_954987.2
TH	XM_011520335.3	c.324+1G>A		splice_donor_variant			XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.312+1G>A		splice_donor_variant		1	NM_000360.4	ENSP00000325951	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 16, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with TH-related conditions. ClinVar contains an entry for this variant (Variation ID: 555288). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the TH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TH are known to be pathogenic (PMID: 22264700, 24753243). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.89		Position offset: 10
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554923802; hg19: chr11-2190879; COSMIC: COSV100147163; COSMIC: COSV100147163;