11-2167445-T-C

Variant names:

• chr11-2167445-T-C
• rs778613708
• NM_000360.4:c.685A>G

Variant summary

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

The NM_000360.4(TH):​c.685A>G​(p.Ile229Val) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21

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=0.16210952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.685A>G	p.Ile229Val	missense_variant	Exon 6 of 13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.778A>G	p.Ile260Val	missense_variant	Exon 7 of 14		NP_954986.2
TH	NM_199293.3	c.766A>G	p.Ile256Val	missense_variant	Exon 7 of 14		NP_954987.2
TH	XM_011520335.3	c.697A>G	p.Ile233Val	missense_variant	Exon 6 of 13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.685A>G	p.Ile229Val	missense_variant	Exon 6 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000860 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Uncertain	0.60	D;.;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.85	D;D;T;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	0.80	N;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.090	N;N;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.48	T;T;.;T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.14
MutPred		0.51		Loss of catalytic residue at I260 (P = 0.0895);.;.;.;
MVP		0.55
MPC		0.041
ClinPred		0.11	T
GERP RS		1.0
Varity_R		0.17
gMVP		0.40

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: rs778613708; hg19: chr11-2188675;