11-2166492-C-T

Variant names:

• chr11-2166492-C-T
• NM_000360.4:c.1035G>A
• TH p.Ala345Ala

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP7

The NM_000360.4(TH):​c.1035G>A​(p.Ala345Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A345A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TH NM_000360.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.70
• 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• tyrosine hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women's Health

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP7: Synonymous conserved (PhyloP=-2.7 with no splicing effect.

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.1035G>A	p.Ala345Ala	synonymous	Exon 9 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.1128G>A	p.Ala376Ala	synonymous	Exon 10 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.1116G>A	p.Ala372Ala	synonymous	Exon 10 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.1035G>A	p.Ala345Ala	synonymous	Exon 9 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.1128G>A	p.Ala376Ala	synonymous	Exon 10 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.1116G>A	p.Ala372Ala	synonymous	Exon 10 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1439654 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 715452

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.00 AC: 0 AN: 43160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 39156

South Asian (SAS) AF: 0.00 AC: 0 AN: 83952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107092

Other (OTH) AF: 0.00 AC: 0 AN: 59636

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.8
DANN	Benign	0.95
PhyloP100		-2.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-2187722;