rs377729019

chr11-2167477-G-Achr11-2167477-G-Cchr11-2167477-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000360.4(TH):c.653C>T(p.Pro218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,561,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P218S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.89

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 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000360.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42371455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TH	NM_000360.4	c.653C>T	p.Pro218Leu	missense_variant	6/13	ENST00000352909.8
TH	NM_199292.3	c.746C>T	p.Pro249Leu	missense_variant	7/14
TH	NM_199293.3	c.734C>T	p.Pro245Leu	missense_variant	7/14
TH	XM_011520335.3	c.665C>T	p.Pro222Leu	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8	c.653C>T	p.Pro218Leu	missense_variant	6/13	1	NM_000360.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000414 AC: 7 AN: 168990 Hom.: 0 AF XY: 0.0000334 AC XY: 3 AN XY: 89836

Gnomad AFR exome AF: 0.000305

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000231

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000248 AC: 35 AN: 1409122 Hom.: 0 Cov.: 33 AF XY: 0.0000287 AC XY: 20 AN XY: 695938

Gnomad4 AFR exome AF: 0.000124

Gnomad4 AMR exome AF: 0.0000538

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000808

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000157

Gnomad4 OTH exome AF: 0.0000685

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74466

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.000463 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000436 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 2021	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 249 of the TH protein (p.Pro249Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with generalized dystonia (PMID: 29801903). ClinVar contains an entry for this variant (Variation ID: 374731). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 03, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 11, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 23, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.3	D;D;.;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.015	D;D;.;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.97	D;D;.;P
Vest4		0.28
MVP		0.93
MPC		0.16
ClinPred		0.31	T
GERP RS		2.5
Varity_R		0.63
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377729019; hg19: chr11-2188707;