rs878855308

chr11-2166999-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000360.4(TH):c.729C>T(p.Tyr243=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 1,588,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.145

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 11-2166999-G-A is Benign according to our data. Variant chr11-2166999-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 242256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.145 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TH	NM_000360.4	c.729C>T	p.Tyr243=	synonymous_variant	7/13	ENST00000352909.8
TH	NM_199292.3	c.822C>T	p.Tyr274=	synonymous_variant	8/14
TH	NM_199293.3	c.810C>T	p.Tyr270=	synonymous_variant	8/14
TH	XM_011520335.3	c.741C>T	p.Tyr247=	synonymous_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8	c.729C>T	p.Tyr243=	synonymous_variant	7/13	1	NM_000360.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000278 AC: 40 AN: 1436536 Hom.: 0 Cov.: 65 AF XY: 0.0000267 AC XY: 19 AN XY: 712304

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000169

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.0000199

Gnomad4 NFE exome AF: 0.0000236

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2020

- -

Autosomal recessive DOPA responsive dystonia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	6.3
Dann	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878855308; hg19: chr11-2188229;