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:5
• 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• hawkinsinuria

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

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

Selected	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
	HPD	NM_001171993.2		c.901G>T	p.Val301Leu	missense	Exon 15 of 16	NP_001165464.1

Ensembl Transcripts

Selected	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
	HPD	ENST00000543163.5	TSL:5	c.901G>T	p.Val301Leu	missense	Exon 14 of 15	ENSP00000441677.1

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 21, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hawkinsinuria Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Tyrosinemia type III Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Tyrosinemia type III;C2931042:Hawkinsinuria Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;