rs74555599

chr11-2171771-C-Achr11-2171771-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000360.4(TH):c.16G>T(p.Ala6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. A6T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.166

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15513897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TH	NM_000360.4	c.16G>T	p.Ala6Ser	missense_variant	1/13	ENST00000352909.8
TH	NM_199292.3	c.16G>T	p.Ala6Ser	missense_variant	1/14
TH	NM_199293.3	c.16G>T	p.Ala6Ser	missense_variant	1/14
TH	XM_011520335.3	c.16G>T	p.Ala6Ser	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8	c.16G>T	p.Ala6Ser	missense_variant	1/13	1	NM_000360.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000811 AC: 2 AN: 246498 Hom.: 0 AF XY: 0.00000748 AC XY: 1 AN XY: 133724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459956 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

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

ExAC AF: 0.00000824 AC: 1

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

Invitae

Aug 09, 2022

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 sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 6 of the TH protein (p.Ala6Ser). This variant has not been reported in the literature in individuals affected with TH-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TH protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	0.80
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	0.43	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.12	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.73	T;T;T;T
Polyphen		0.0080	B;B;.;B
Vest4		0.072
MutPred		0.13		Gain of glycosylation at A6 (P = 0.0012);Gain of glycosylation at A6 (P = 0.0012);Gain of glycosylation at A6 (P = 0.0012);Gain of glycosylation at A6 (P = 0.0012);
MVP		0.76
MPC		0.050
ClinPred		0.10	T
GERP RS		-1.8
Varity_R		0.056
gMVP		0.21

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: rs74555599; hg19: chr11-2193001;