rs780478399

Variant names:

• chr11-2169769-C-A
• NM_000360.4:c.193G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000360.4(TH):​c.193G>T​(p.Gly65Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,628 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.193G>T	p.Gly65Trp	missense_variant	Exon 2 of 13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.286G>T	p.Gly96Trp	missense_variant	Exon 3 of 14		NP_954986.2
TH	NM_199293.3	c.274G>T	p.Gly92Trp	missense_variant	Exon 3 of 14		NP_954987.2
TH	XM_011520335.3	c.205G>T	p.Gly69Trp	missense_variant	Exon 2 of 13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.193G>T	p.Gly65Trp	missense_variant	Exon 2 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459628 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 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: 0.00

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	0.19
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.;.
Eigen	Benign	-0.0099
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N;N;.;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.42
MutPred		0.29		Loss of helix (P = 0.0444);.;.;.;
MVP		0.96
MPC		0.32
ClinPred		0.81	D
GERP RS		3.5
Varity_R		0.29
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2190999;