11-2171764-G-T

Variant names:

• chr11-2171764-G-T
• rs373964946
• NM_000360.4:c.23C>A

Variant summary

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

The NM_000360.4(TH):​c.23C>A​(p.Thr8Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.21

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=0.35497385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.23C>A	p.Thr8Lys	missense_variant	Exon 1 of 13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.23C>A	p.Thr8Lys	missense_variant	Exon 1 of 14		NP_954986.2
TH	NM_199293.3	c.23C>A	p.Thr8Lys	missense_variant	Exon 1 of 14		NP_954987.2
TH	XM_011520335.3	c.23C>A	p.Thr8Lys	missense_variant	Exon 1 of 13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.23C>A	p.Thr8Lys	missense_variant	Exon 1 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460304 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726530

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.37	T;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	0.81	L;L;L;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.95	N;N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.030	D;T;T;T
Polyphen		0.41	B;B;.;B
Vest4		0.32
MutPred		0.19		Loss of phosphorylation at T8 (P = 0.0061);Loss of phosphorylation at T8 (P = 0.0061);Loss of phosphorylation at T8 (P = 0.0061);Loss of phosphorylation at T8 (P = 0.0061);
MVP		0.93
MPC		0.057
ClinPred		0.40	T
GERP RS		2.9
Varity_R		0.19
gMVP		0.42

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: rs373964946; hg19: chr11-2192994;