12-121839985-C-T

Variant names:

• chr12-121839985-C-T
• rs36023382
• NM_002150.3:c.1018G>A

Variant summary

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

The NM_002150.3(HPD):​c.1018G>A​(p.Val340Met) 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 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 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. V340L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HPD NM_002150.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13

Genes affected

HPD (HGNC:5147): (4-hydroxyphenylpyruvate dioxygenase) The protein encoded by this gene is an enzyme in the catabolic pathway of tyrosine. The encoded protein catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. Defects in this gene are a cause of tyrosinemia type 3 (TYRO3) and hawkinsinuria (HAWK). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

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=0.15674937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPD	NM_002150.3	c.1018G>A	p.Val340Met	missense_variant	Exon 13 of 14	ENST00000289004.8	NP_002141.2
HPD	NM_001171993.2	c.901G>A	p.Val301Met	missense_variant	Exon 15 of 16		NP_001165464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPD	ENST00000289004.8	c.1018G>A	p.Val340Met	missense_variant	Exon 13 of 14	1	NM_002150.3	ENSP00000289004.4
HPD	ENST00000543163.5	c.901G>A	p.Val301Met	missense_variant	Exon 14 of 15	5		ENSP00000441677.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.33	N;N
REVEL	Benign	0.028
Sift	Benign	0.30	T;T
Sift4G	Benign	0.32	T;T
Vest4		0.15
MutPred		0.38		Gain of catalytic residue at K338 (P = 0.0012);.;
MVP		0.58
MPC		0.38
ClinPred		0.46	T
GERP RS		-0.54
gMVP		0.63

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: rs36023382; hg19: chr12-122277891;