rs6356

Positions:

• chr11-2169721-C-A
• chr11-2169721-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.241G>T​(p.Val81Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. V81M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.303

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=0.16418833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.241G>T	p.Val81Leu	missense_variant	2/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.334G>T	p.Val112Leu	missense_variant	3/14		NP_954986.2
TH	NM_199293.3	c.322G>T	p.Val108Leu	missense_variant	3/14		NP_954987.2
TH	XM_011520335.3	c.253G>T	p.Val85Leu	missense_variant	2/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.241G>T	p.Val81Leu	missense_variant	2/13	1	NM_000360.4	ENSP00000325951	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.067
DANN	Benign	0.93
DEOGEN2	Benign	0.25	T;.;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.58	N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.040	N;N;.;N
REVEL	Benign	0.10
Sift	Benign	0.34	T;T;.;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.047
MutPred		0.28		Gain of disorder (P = 0.0906);.;.;.;
MVP		0.85
MPC		0.045
ClinPred		0.091	T
GERP RS		-1.8
Varity_R		0.050
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6356; hg19: chr11-2190951;