rs28934580

Positions:

• chr11-2166693-C-A
• chr11-2166693-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000360.4(TH):​c.917G>T​(p.Arg306Leu) variant causes a missense change involving the alteration of a 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.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.917G>T	p.Arg306Leu	missense_variant	8/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1010G>T	p.Arg337Leu	missense_variant	9/14		NP_954986.2
TH	NM_199293.3	c.998G>T	p.Arg333Leu	missense_variant	9/14		NP_954987.2
TH	XM_011520335.3	c.929G>T	p.Arg310Leu	missense_variant	8/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.917G>T	p.Arg306Leu	missense_variant	8/13	1	NM_000360.4	ENSP00000325951	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1406608 Hom.: 0 Cov.: 63 AF XY: 0.00 AC XY: 0 AN XY: 694580

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.4	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.90
MutPred		0.85		Loss of catalytic residue at R337 (P = 0.003);.;.;
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28934580; hg19: chr11-2187923;