rs538345855

chr11-2168674-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000360.4(TH):c.313-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000877 in 1,352,854 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00091 (13 hom.)
• Consequence: TH NM_000360.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003605
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.105

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-2168674-G-A is Benign according to our data. Variant chr11-2168674-G-A is described in ClinVar as [Benign]. Clinvar id is 304082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2168674-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000527 (70/132842) while in subpopulation SAS AF= 0.0168 (66/3936). AF 95% confidence interval is 0.0135. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TH	NM_000360.4	c.313-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000352909.8
TH	NM_199292.3	c.406-9C>T		splice_polypyrimidine_tract_variant, intron_variant
TH	NM_199293.3	c.394-9C>T		splice_polypyrimidine_tract_variant, intron_variant
TH	XM_011520335.3	c.325-9C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8	c.313-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000360.4	P1

Frequencies

GnomAD3 genomes AF: 0.000527 AC: 70 AN: 132766 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000156

Gnomad OTH AF: 0.000532

GnomAD3 exomes AF: 0.00161 AC: 381 AN: 236764 Hom.: 4 AF XY: 0.00216 AC XY: 282 AN XY: 130302

Gnomad AFR exome AF: 0.0000717

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0123

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000287

Gnomad OTH exome AF: 0.000863

GnomAD4 exome AF: 0.000915 AC: 1116 AN: 1220012 Hom.: 13 Cov.: 34 AF XY: 0.00128 AC XY: 776 AN XY: 604544

Gnomad4 AFR exome AF: 0.000113

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000752

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.000527 AC: 70 AN: 132842 Hom.: 0 Cov.: 31 AF XY: 0.000890 AC XY: 56 AN XY: 62916

Gnomad4 AFR AF: 0.0000553

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000156

Gnomad4 OTH AF: 0.000527

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000117

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 12, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	3.1
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs538345855; hg19: chr11-2189904; COSMIC: COSV60767535; COSMIC: COSV60767535;