chr12-121839985-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.13

Publications

10 publications found

Variant links:

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

HPD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPD	NM_002150.3 link	c.1018G>T	p.Val340Leu	missense_variant	Exon 13 of 14	ENST00000289004.8	NP_002141.2	P32754
HPD	NM_001171993.2 link	c.901G>T	p.Val301Leu	missense_variant	Exon 15 of 16		NP_001165464.1	P32754-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPD	ENST00000289004.8 link	c.1018G>T	p.Val340Leu	missense_variant	Exon 13 of 14	1	NM_002150.3	ENSP00000289004.4		A0A0B4J1R4
HPD	ENST00000543163.5 link	c.901G>T	p.Val301Leu	missense_variant	Exon 14 of 15	5		ENSP00000441677.1		P32754-2

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1924

AN:

151814

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00895

AC XY:

6506

AN XY:

727224

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

821

1642

2464

3285

4106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

244

488

732

976

1220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0127

AC:

1924

AN:

151932

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

982

AN XY:

74256

show subpopulations

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:

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:

AN:

286

European-Non Finnish (NFE)

AF:

0.00493

AC:

335

AN:

67932

Other (OTH)

AF:

0.0190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

176

265

353

441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00901

Hom.:

Bravo

AF:

0.0134

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.0157

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.0134

AC:

1630

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.00796

EpiControl

AF:

0.00717

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 21, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0082

T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-1.1

PhyloP100

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.33

N;N

REVEL

Benign

0.066

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);.;

MPC

0.37

ClinPred

0.029

GERP RS

-0.54

gMVP

0.59

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over