11-2166625-G-A

Variant names:

• chr11-2166625-G-A
• rs12419447
• NM_000360.4:c.977+8C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000360.4(TH):​c.977+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000841 in 1,426,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: TH NM_000360.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001110
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0860
• Publications: 14 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 11-2166625-G-A is Benign according to our data. Variant chr11-2166625-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 662187.

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.977+8C>T		splice_region intron	N/A	NP_000351.2	P07101-3
	TH	NM_199292.3		c.1070+8C>T		splice_region intron	N/A	NP_954986.2	P07101-1
	TH	NM_199293.3		c.1058+8C>T		splice_region intron	N/A	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.977+8C>T		splice_region intron	N/A	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.1070+8C>T		splice_region intron	N/A	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.1058+8C>T		splice_region intron	N/A	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000841 AC: 12 AN: 1426436 Hom.: 0 Cov.: 78 AF XY: 0.00000708 AC XY: 5 AN XY: 706314

African (AFR) AF: 0.00 AC: 0 AN: 33012

American (AMR) AF: 0.00 AC: 0 AN: 38780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25428

East Asian (EAS) AF: 0.00 AC: 0 AN: 38190

South Asian (SAS) AF: 0.00 AC: 0 AN: 81626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000110 AC: 12 AN: 1095428

Other (OTH) AF: 0.00 AC: 0 AN: 59114

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 2477

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive DOPA responsive dystonia (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.1
DANN	Uncertain	0.98
PhyloP100		-0.086

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
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

Other links and lift over

dbSNP: rs12419447; hg19: chr11-2187855;