rs780478399

Positions:

• chr11-2169769-C-G
• chr11-2169769-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000360.4(TH):​c.193G>C​(p.Gly65Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.813

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35990256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.193G>C	p.Gly65Arg	missense_variant	2/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.286G>C	p.Gly96Arg	missense_variant	3/14		NP_954986.2
TH	NM_199293.3	c.274G>C	p.Gly92Arg	missense_variant	3/14		NP_954987.2
TH	XM_011520335.3	c.205G>C	p.Gly69Arg	missense_variant	2/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.193G>C	p.Gly65Arg	missense_variant	2/13	1	NM_000360.4	ENSP00000325951	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243524 Hom.: 0 AF XY: 0.00000751 AC XY: 1 AN XY: 133118

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459628 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2 AN XY: 726088

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

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	Benign	0.12
BayesDel_addAF	Benign	0.0038	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;.;.;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N;N;.;N
REVEL	Uncertain	0.42
Sift	Benign	0.052	T;D;.;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.98	D;D;.;D
Vest4		0.29
MutPred		0.27		Gain of solvent accessibility (P = 0.0037);.;.;.;
MVP		0.91
MPC		0.054
ClinPred		0.22	T
GERP RS		3.5
Varity_R		0.18
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs780478399; hg19: chr11-2190999;