12-121858702-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002150.3(HPD):c.15T>G(p.Ser5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.006 in 1,613,958 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 159 hom. )

Consequence

HPD
NM_002150.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.319

Publications

7 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:

TIALD (HGNC:56938):

TIALD 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=0.0028541684).

BP6

Variant 12-121858702-A-C is Benign according to our data. Variant chr12-121858702-A-C is described in ClinVar as Benign. ClinVar VariationId is 235261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.065 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPD	NM_002150.3 link	c.15T>G	p.Ser5Arg	missense_variant	Exon 2 of 14	ENST00000289004.8	NP_002141.2	P32754
HPD	NM_001171993.2 link	c.-103T>G		5_prime_UTR_variant	Exon 4 of 16		NP_001165464.1	P32754-2
TIALD	XR_002957437.2 link	n.614+864A>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPD	ENST00000289004.8 link	c.15T>G	p.Ser5Arg	missense_variant	Exon 2 of 14	1	NM_002150.3	ENSP00000289004.4		A0A0B4J1R4

Frequencies

GnomAD3 genomes

AF:

0.00653

AC:

992

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0294

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.00161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00585

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.0142

AC:

3560

AN:

251476

AF XY:

0.0121

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.0735

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00537

Gnomad OTH exome

AF:

0.00945

GnomAD4 exome

AF:

0.00593

AC:

8675

AN:

1461834

Hom.:

159

Cov.:

AF XY:

0.00593

AC XY:

4314

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33480

American (AMR)

AF:

0.0670

AC:

2998

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00955

AC:

824

AN:

86254

European-Finnish (FIN)

AF:

0.00154

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00798

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00386

AC:

4296

AN:

1111964

Other (OTH)

AF:

0.00546

AC:

330

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

563

1126

1690

2253

2816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.00659

AC:

1003

AN:

152124

Hom.:

Cov.:

AF XY:

0.00678

AC XY:

504

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41494

American (AMR)

AF:

0.0301

AC:

460

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.0104

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00585

AC:

398

AN:

67996

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00647

Hom.:

Bravo

AF:

0.00874

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.0126

AC:

1532

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.00502

EpiControl

AF:

0.00563

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 17, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

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

- -

Aug 13, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hawkinsinuria

Benign:1

Jan 13, 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 13, 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 29, 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

0.32

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.027

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.1

PhyloP100

-0.32

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.4

REVEL

Benign

0.061

Sift

Benign

0.040

Sift4G

Benign

0.16

Vest4

0.13

MutPred

0.26

Loss of ubiquitination at K7 (P = 0.0192);

MPC

0.47

ClinPred

0.00098

GERP RS

-3.7

PromoterAI

0.035

Neutral

(source)

gMVP

0.29

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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