rs886038763

Variant names:

• chr11-2168636-C-T
• rs886038763
• NM_000360.4:c.342G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000360.4(TH):​c.342G>A​(p.Glu114Glu) variant causes a synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.62
• 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: Likely_benign. 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=-0.44).
• BP6: Variant 11-2168636-C-T is Benign according to our data. Variant chr11-2168636-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263256.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000360.4. 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.342G>A	p.Glu114Glu	synonymous	Exon 3 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.435G>A	p.Glu145Glu	synonymous	Exon 4 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.423G>A	p.Glu141Glu	synonymous	Exon 4 of 14	NP_954987.2	P07101-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.342G>A	p.Glu114Glu	synonymous	Exon 3 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.435G>A	p.Glu145Glu	synonymous	Exon 4 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.423G>A	p.Glu141Glu	synonymous	Exon 4 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		3.6

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

Other links and lift over

dbSNP: rs886038763; hg19: chr11-2189866;