11-2167477-G-T

Variant names:

• chr11-2167477-G-T
• rs377729019
• NM_000360.4:c.653C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000360.4(TH):​c.653C>A​(p.Pro218Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P218L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.89
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• tyrosine hydroxylase deficiency

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

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_000360.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.653C>A	p.Pro218Gln	missense	Exon 6 of 13	NP_000351.2
	TH	NM_199292.3		c.746C>A	p.Pro249Gln	missense	Exon 7 of 14	NP_954986.2
	TH	NM_199293.3		c.734C>A	p.Pro245Gln	missense	Exon 7 of 14	NP_954987.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.653C>A	p.Pro218Gln	missense	Exon 6 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.746C>A	p.Pro249Gln	missense	Exon 7 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.734C>A	p.Pro245Gln	missense	Exon 7 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 168990 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1409118 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 695938

African (AFR) AF: 0.00 AC: 0 AN: 32382

American (AMR) AF: 0.00 AC: 0 AN: 37184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25240

East Asian (EAS) AF: 0.00 AC: 0 AN: 37108

South Asian (SAS) AF: 0.00 AC: 0 AN: 80082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084654

Other (OTH) AF: 0.00 AC: 0 AN: 58382

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.9
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.026	D
Polyphen		0.94	P
Vest4		0.52
MutPred		0.67		Gain of solvent accessibility (P = 0.0739)
MVP		0.93
MPC		0.26
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.51
gMVP		0.63
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs377729019; hg19: chr11-2188707;