rs536382000

chr11-2167451-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The NM_000360.4(TH):c.679G>A(p.Glu227Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000497 in 1,563,464 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E227A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (7 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 5.34

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 Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000360.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.032366574).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000522 (737/1411202) while in subpopulation SAS AF= 0.00548 (439/80130). AF 95% confidence interval is 0.00506. There are 7 homozygotes in gnomad4_exome. There are 475 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TH	NM_000360.4	c.679G>A	p.Glu227Lys	missense_variant	6/13	ENST00000352909.8
TH	NM_199292.3	c.772G>A	p.Glu258Lys	missense_variant	7/14
TH	NM_199293.3	c.760G>A	p.Glu254Lys	missense_variant	7/14
TH	XM_011520335.3	c.691G>A	p.Glu231Lys	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8	c.679G>A	p.Glu227Lys	missense_variant	6/13	1	NM_000360.4	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000987 AC: 171 AN: 173190 Hom.: 3 AF XY: 0.00137 AC XY: 126 AN XY: 92088

Gnomad AFR exome AF: 0.0000986

Gnomad AMR exome AF: 0.000113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00595

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.000522 AC: 737 AN: 1411202 Hom.: 7 Cov.: 33 AF XY: 0.000681 AC XY: 475 AN XY: 697234

Gnomad4 AFR exome AF: 0.000154

Gnomad4 AMR exome AF: 0.0000534

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.00548

Gnomad4 FIN exome AF: 0.0000206

Gnomad4 NFE exome AF: 0.000211

Gnomad4 OTH exome AF: 0.000702

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74448

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000490 AC: 57

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Uncertain:3 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.
Eigen	Benign	0.083
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.032	T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0080	D;D;T;D
Sift4G	Benign	0.066	T;T;D;D
Polyphen		0.79	P;P;.;P
Vest4		0.56
MVP		0.96
MPC		0.21
ClinPred		0.14	T
GERP RS		3.4
Varity_R		0.83
gMVP		0.76

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: rs536382000; hg19: chr11-2188681; COSMIC: COSV100147036; COSMIC: COSV100147036;