NM_000360.4:c.1475C>G

Variant names:

• chr11-2164252-G-C
• NM_000360.4:c.1475C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000360.4(TH):​c.1475C>G​(p.Ala492Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,329,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.58

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.1475C>G	p.Ala492Gly	missense_variant	Exon 13 of 13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1568C>G	p.Ala523Gly	missense_variant	Exon 14 of 14		NP_954986.2
TH	NM_199293.3	c.1556C>G	p.Ala519Gly	missense_variant	Exon 14 of 14		NP_954987.2
TH	XM_011520335.3	c.1487C>G	p.Ala496Gly	missense_variant	Exon 13 of 13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1475C>G	p.Ala492Gly	missense_variant	Exon 13 of 13	1	NM_000360.4	ENSP00000325951.4
TH	ENST00000381178.5	c.1568C>G	p.Ala523Gly	missense_variant	Exon 14 of 14	1		ENSP00000370571.1
TH	ENST00000381175.5	c.1556C>G	p.Ala519Gly	missense_variant	Exon 14 of 14	1		ENSP00000370567.1
TH	ENST00000333684.9	c.1193C>G	p.Ala398Gly	missense_variant	Exon 11 of 11	1		ENSP00000328814.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1329660 Hom.: 0 Cov.: 30 AF XY: 0.00000154 AC XY: 1 AN XY: 650812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000363

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D;D;.;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;D;.;D
Vest4		0.66
MutPred		0.75		Gain of disorder (P = 0.0961);.;.;.;
MVP		0.99
MPC		1.5
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.87
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-2185482;