rs11833399

Variant names:

• chr12-121854779-C-T
• rs11833399
• NM_002150.3:c.338G>A
• HPD p.Arg113Gln

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002150.3(HPD):​c.338G>A​(p.Arg113Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,613,794 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (101 hom.)
• Consequence: HPD NM_002150.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.96
• Publications: 7 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• 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=0.004478991).
• BP6: Variant 12-121854779-C-T is Benign according to our data. Variant chr12-121854779-C-T is described in ClinVar as Benign. ClinVar VariationId is 307486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0701 is higher than 0.05.

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.338G>A	p.Arg113Gln	missense	Exon 7 of 14	NP_002141.2	P32754-1
	HPD	NM_001171993.2		c.221G>A	p.Arg74Gln	missense	Exon 9 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.338G>A	p.Arg113Gln	missense	Exon 7 of 14	ENSP00000289004.4	P32754-1
	HPD	ENST00000868949.1		c.338G>A	p.Arg113Gln	missense	Exon 7 of 15	ENSP00000539008.1
	HPD	ENST00000868952.1		c.338G>A	p.Arg113Gln	missense	Exon 7 of 14	ENSP00000539011.1

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3228 AN: 152122 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00712 AC: 1791 AN: 251492 AF XY: 0.00616

Gnomad AFR exome AF: 0.0789

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00297 AC: 4348 AN: 1461554 Hom.: 101 Cov.: 31 AF XY: 0.00299 AC XY: 2176 AN XY: 727116

African (AFR) AF: 0.0806 AC: 2697 AN: 33458

American (AMR) AF: 0.00376 AC: 168 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39694

South Asian (SAS) AF: 0.0101 AC: 868 AN: 86248

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53410

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.000192 AC: 213 AN: 1111746

Other (OTH) AF: 0.00593 AC: 358 AN: 60374

GnomAD4 genome AF: 0.0212 AC: 3231 AN: 152240 Hom.: 94 Cov.: 32 AF XY: 0.0202 AC XY: 1502 AN XY: 74438

African (AFR) AF: 0.0723 AC: 3001 AN: 41526

American (AMR) AF: 0.00727 AC: 111 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68032

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.00826 Hom.: 116

Bravo AF: 0.0246

Asia WGS AF: 0.0170 AC: 61 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.0
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.076
Sift	Benign	0.20	T
Sift4G	Benign	0.21	T
gMVP		0.62
Mutation Taster		=92/8	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11833399;

hg19: chr12-122292685;

COSMIC: COSV56642447;

COSMIC: COSV56642447;