11-2171568-C-A

Variant names:

• chr11-2171568-C-A
• rs10840489
• NM_000360.4:c.90+129G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000360.4(TH):​c.90+129G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000121 in 829,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: TH NM_000360.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.13
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).

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.90+129G>T		intron	N/A	NP_000351.2	P07101-3
	TH	NM_199292.3		c.102+117G>T		intron	N/A	NP_954986.2	P07101-1
	TH	NM_199293.3		c.90+129G>T		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.90+129G>T		intron	N/A	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.102+117G>T		intron	N/A	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.90+129G>T		intron	N/A	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000121 AC: 1 AN: 829692 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 429418

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21014

American (AMR) AF: 0.00 AC: 0 AN: 34534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20778

East Asian (EAS) AF: 0.00 AC: 0 AN: 33098

South Asian (SAS) AF: 0.00 AC: 0 AN: 67538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3026

European-Non Finnish (NFE) AF: 0.00000173 AC: 1 AN: 577654

Other (OTH) AF: 0.00 AC: 0 AN: 38878

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.059
DANN	Benign	0.42
PhyloP100		-5.1
PromoterAI		0.0073	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs10840489; hg19: chr11-2192798;