rs28934581

Variant names:

• chr11-2166995-T-G
• rs28934581
• NM_000360.4:c.733A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000360.4(TH):​c.733A>C​(p.Thr245Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000765 in 1,437,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 4.67
• Publications: 12 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

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.733A>C	p.Thr245Pro	missense	Exon 7 of 13	NP_000351.2
	TH	NM_199292.3		c.826A>C	p.Thr276Pro	missense	Exon 8 of 14	NP_954986.2
	TH	NM_199293.3		c.814A>C	p.Thr272Pro	missense	Exon 8 of 14	NP_954987.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.733A>C	p.Thr245Pro	missense	Exon 7 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.826A>C	p.Thr276Pro	missense	Exon 8 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.814A>C	p.Thr272Pro	missense	Exon 8 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000146 AC: 3 AN: 205448 AF XY: 0.0000180

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: 0.0000338

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000765 AC: 11 AN: 1437338 Hom.: 0 Cov.: 63 AF XY: 0.00000561 AC XY: 4 AN XY: 712754

African (AFR) AF: 0.00 AC: 0 AN: 33052

American (AMR) AF: 0.00 AC: 0 AN: 41576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25600

East Asian (EAS) AF: 0.00 AC: 0 AN: 38492

South Asian (SAS) AF: 0.00 AC: 0 AN: 82556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1100478

Other (OTH) AF: 0.00 AC: 0 AN: 59474

GnomAD4 genome Cov.: 34

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000835 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	-	Autosomal recessive DOPA responsive dystonia (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.016	D
Polyphen		0.90	P
Vest4		0.60
MutPred		0.84		Loss of stability (P = 0.0338)
MVP		0.98
MPC		0.33
ClinPred		0.90	D
GERP RS		3.2
Varity_R		0.96
gMVP		0.84
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs28934581; hg19: chr11-2188225;