rs1554922200

Variant names:

• chr11-2164393-C-T
• rs1554922200
• NM_000360.4:c.1335-1G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000360.4(TH):​c.1335-1G>A variant causes a splice acceptor, intron 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TH NM_000360.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.94

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 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2164393-C-T is Pathogenic according to our data. Variant chr11-2164393-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 552670.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.1335-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 12	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1428-1G>A		splice_acceptor_variant, intron_variant	Intron 13 of 13		NP_954986.2
TH	NM_199293.3	c.1416-1G>A		splice_acceptor_variant, intron_variant	Intron 13 of 13		NP_954987.2
TH	XM_011520335.3	c.1347-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 12		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1335-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 12	1	NM_000360.4	ENSP00000325951.4
TH	ENST00000381178.5	c.1428-1G>A		splice_acceptor_variant, intron_variant	Intron 13 of 13	1		ENSP00000370571.1
TH	ENST00000381175.5	c.1416-1G>A		splice_acceptor_variant, intron_variant	Intron 13 of 13	1		ENSP00000370567.1
TH	ENST00000333684.9	c.1053-1G>A		splice_acceptor_variant, intron_variant	Intron 10 of 10	1		ENSP00000328814.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395738 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Pathogenic:1 Uncertain:1

Feb 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -2
DS_AL_spliceai		1.0		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: rs1554922200; hg19: chr11-2185623;