11-2164238-C-T

Position:

• chr11-2164238-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000360.4(TH):​c.1489G>A​(p.Gly497Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000763 in 1,311,350 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.890

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04024604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.1489G>A	p.Gly497Ser	missense_variant	13/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1582G>A	p.Gly528Ser	missense_variant	14/14		NP_954986.2
TH	NM_199293.3	c.1570G>A	p.Gly524Ser	missense_variant	14/14		NP_954987.2
TH	XM_011520335.3	c.1501G>A	p.Gly501Ser	missense_variant	13/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1489G>A	p.Gly497Ser	missense_variant	13/13	1	NM_000360.4	ENSP00000325951.4
TH	ENST00000381178.5	c.1582G>A	p.Gly528Ser	missense_variant	14/14	1		ENSP00000370571.1
TH	ENST00000381175.5	c.1570G>A	p.Gly524Ser	missense_variant	14/14	1		ENSP00000370567.1
TH	ENST00000333684.9	c.1207G>A	p.Gly403Ser	missense_variant	11/11	1		ENSP00000328814.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.63e-7 AC: 1 AN: 1311350 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 640532

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: 9.66e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	0.041
DANN	Benign	0.94
DEOGEN2	Benign	0.22	T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.040	T;T;T;T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	-0.73	N;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.76	N;N;.;N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T;T;.;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.0030	B;B;.;B
Vest4		0.079
MutPred		0.24		Gain of glycosylation at G528 (P = 0.0366);.;.;.;
MVP		0.38
MPC		0.58
ClinPred		0.17	T
GERP RS		-2.5
Varity_R		0.14
gMVP		0.40

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: chr11-2185468;