12-121839985-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002150.3(HPD):​c.1018G>T​(p.Val340Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00879 in 1,613,768 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V340E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (175 hom.)
• Consequence: HPD NM_002150.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.13
• Publications: 10 publications found

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]

HPD Gene-Disease associations (from GenCC):

• tyrosinemia type III

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hawkinsinuria

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036437213).
• BP6: Variant 12-121839985-C-A is Benign according to our data. Variant chr12-121839985-C-A is described in ClinVar as Benign. ClinVar VariationId is 307478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0127 (1924/151932) while in subpopulation SAS AF = 0.0231 (111/4814). AF 95% confidence interval is 0.0196. There are 34 homozygotes in GnomAd4. There are 982 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002150.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPD	NM_002150.3	MANE Select	c.1018G>T	p.Val340Leu	missense	Exon 13 of 14	NP_002141.2	P32754-1
	HPD	NM_001171993.2		c.901G>T	p.Val301Leu	missense	Exon 15 of 16	NP_001165464.1	P32754-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPD	ENST00000289004.8	TSL:1 MANE Select	c.1018G>T	p.Val340Leu	missense	Exon 13 of 14	ENSP00000289004.4	P32754-1
	HPD	ENST00000868949.1		c.1159G>T	p.Val387Leu	missense	Exon 14 of 15	ENSP00000539008.1
	HPD	ENST00000868952.1		c.1069G>T	p.Val357Leu	missense	Exon 13 of 14	ENSP00000539011.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1924 AN: 151814 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0292

Gnomad NFE AF: 0.00495

Gnomad OTH AF: 0.0173

GnomAD2 exomes AF: 0.0140 AC: 3528 AN: 251486 AF XY: 0.0145

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0636

Gnomad EAS exome AF: 0.0173

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.00574

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.00838 AC: 12256 AN: 1461836 Hom.: 175 Cov.: 31 AF XY: 0.00895 AC XY: 6506 AN XY: 727224

African (AFR) AF: 0.0201 AC: 673 AN: 33480

American (AMR) AF: 0.0114 AC: 510 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0650 AC: 1698 AN: 26136

East Asian (EAS) AF: 0.0160 AC: 634 AN: 39700

South Asian (SAS) AF: 0.0230 AC: 1981 AN: 86258

European-Finnish (FIN) AF: 0.0146 AC: 781 AN: 53414

Middle Eastern (MID) AF: 0.0317 AC: 183 AN: 5766

European-Non Finnish (NFE) AF: 0.00445 AC: 4943 AN: 1111964

Other (OTH) AF: 0.0141 AC: 853 AN: 60394

GnomAD4 genome AF: 0.0127 AC: 1924 AN: 151932 Hom.: 34 Cov.: 32 AF XY: 0.0132 AC XY: 982 AN XY: 74256

African (AFR) AF: 0.0183 AC: 757 AN: 41434

American (AMR) AF: 0.0117 AC: 179 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 238 AN: 3468

East Asian (EAS) AF: 0.0181 AC: 93 AN: 5134

South Asian (SAS) AF: 0.0231 AC: 111 AN: 4814

European-Finnish (FIN) AF: 0.0153 AC: 162 AN: 10578

Middle Eastern (MID) AF: 0.0315 AC: 9 AN: 286

European-Non Finnish (NFE) AF: 0.00493 AC: 335 AN: 67932

Other (OTH) AF: 0.0190 AC: 40 AN: 2108

Alfa AF: 0.00901 Hom.: 53

Bravo AF: 0.0134

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.0134 AC: 1630

Asia WGS AF: 0.0230 AC: 83 AN: 3478

EpiCase AF: 0.00796

EpiControl AF: 0.00717

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hawkinsinuria (1)
-	-	1	Tyrosinemia type III (1)
-	-	1	Tyrosinemia type III;C2931042:Hawkinsinuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.47	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
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.066
Sift	Benign	0.52	T
Sift4G	Benign	0.61	T
Vest4		0.11
MutPred		0.22		Gain of catalytic residue at V340 (P = 8e-04)
MPC		0.37
ClinPred		0.029	T
GERP RS		-0.54
gMVP		0.59
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs36023382; hg19: chr12-122277891; COSMIC: COSV56643879;