rs184106392

Positions:

• chr11-2165311-C-G
• chr11-2165311-C-T

Variant summary

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

The NM_000360.4(TH):​c.1255G>C​(p.Val419Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,362 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V419M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.650

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.1255G>C	p.Val419Leu	missense_variant	12/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1348G>C	p.Val450Leu	missense_variant	13/14		NP_954986.2
TH	NM_199293.3	c.1336G>C	p.Val446Leu	missense_variant	13/14		NP_954987.2
TH	XM_011520335.3	c.1267G>C	p.Val423Leu	missense_variant	12/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1255G>C	p.Val419Leu	missense_variant	12/13	1	NM_000360.4	ENSP00000325951	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460362 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726478

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.82	D;.;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.0	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N;N;.;N
REVEL	Uncertain	0.39
Sift	Benign	0.21	T;T;.;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.0020	B;B;.;B
Vest4		0.26
MutPred		0.48		Gain of helix (P = 0.132);.;.;.;
MVP		0.77
MPC		0.58
ClinPred		0.30	T
GERP RS		1.7
Varity_R		0.38
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs184106392; hg19: chr11-2186541;