12-121839985-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002150.3(HPD):​c.1018G>C​(p.Val340Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14544123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPD	NM_002150.3	c.1018G>C	p.Val340Leu	missense_variant	Exon 13 of 14	ENST00000289004.8	NP_002141.2
HPD	NM_001171993.2	c.901G>C	p.Val301Leu	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>C	p.Val340Leu	missense_variant	Exon 13 of 14	1	NM_002150.3	ENSP00000289004.4
HPD	ENST00000543163.5	c.901G>C	p.Val301Leu	missense_variant	Exon 14 of 15	5		ENSP00000441677.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251486 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 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: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

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	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.0082	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.047
Sift	Benign	0.52	T;T
Sift4G	Benign	0.61	T;T
Vest4		0.11
MutPred		0.22		Gain of catalytic residue at V340 (P = 8e-04);.;
MVP		0.55
MPC		0.37
ClinPred		0.22	T
GERP RS		-0.54
gMVP		0.59

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;