11-2168526-A-T

Variant names:

• chr11-2168526-A-T
• NM_000360.4:c.452T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000360.4(TH):​c.452T>A​(p.Val151Glu) 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 1,460,098 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.452T>A	p.Val151Glu	missense_variant	Exon 3 of 13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.545T>A	p.Val182Glu	missense_variant	Exon 4 of 14		NP_954986.2
TH	NM_199293.3	c.533T>A	p.Val178Glu	missense_variant	Exon 4 of 14		NP_954987.2
TH	XM_011520335.3	c.464T>A	p.Val155Glu	missense_variant	Exon 3 of 13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.452T>A	p.Val151Glu	missense_variant	Exon 3 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460098 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726370

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;.;.;.
Eigen	Benign	0.085
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N;N;.;N
REVEL	Pathogenic	0.75
Sift	Benign	0.078	T;T;.;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.94	P;D;.;P
Vest4		0.82
MutPred		0.53		Gain of disorder (P = 0.0212);.;.;.;
MVP		0.98
MPC		0.29
ClinPred		0.86	D
GERP RS		3.7
Varity_R		0.33
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr11-2189756;