rs1154510

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.97A>G(p.Thr33Ala) variant causes a missense change. The variant allele was found at a frequency of 0.866 in 1,607,144 control chromosomes in the GnomAD database, including 604,622 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T33T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.88 ( 59147 hom., cov: 32)

Exomes 𝑓: 0.86 ( 545475 hom. )

Consequence

HPD
NM_002150.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.23

Publications

48 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=2.099031E-6).

BP6

Variant 12-121857429-T-C is Benign according to our data. Variant chr12-121857429-T-C is described in ClinVar as Benign. ClinVar VariationId is 802899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HPD	NM_002150.3 link	c.97A>G	p.Thr33Ala	missense_variant	Exon 4 of 14	ENST00000289004.8	NP_002141.2
HPD	NM_001171993.2 link	c.-21A>G		5_prime_UTR_variant	Exon 6 of 16		NP_001165464.1
TIALD	XR_002957437.2 link	n.395-190T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPD	ENST00000289004.8 link	c.97A>G	p.Thr33Ala	missense_variant	Exon 4 of 14	1	NM_002150.3	ENSP00000289004.4

Frequencies

GnomAD3 genomes

AF:

0.880

AC:

133757

AN:

152062

Hom.:

59095

Cov.:

show subpopulations

Gnomad AFR

AF:

0.960

Gnomad AMI

AF:

0.916

Gnomad AMR

AF:

0.796

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.861

Gnomad SAS

AF:

0.852

Gnomad FIN

AF:

0.769

Gnomad MID

AF:

0.915

Gnomad NFE

AF:

0.869

Gnomad OTH

AF:

0.875

GnomAD2 exomes

AF:

0.845

AC:

212430

AN:

251396

AF XY:

0.848

show subpopulations

Gnomad AFR exome

AF:

0.963

Gnomad AMR exome

AF:

0.728

Gnomad ASJ exome

AF:

0.892

Gnomad EAS exome

AF:

0.863

Gnomad FIN exome

AF:

0.779

Gnomad NFE exome

AF:

0.868

Gnomad OTH exome

AF:

0.855

GnomAD4 exome

AF:

0.865

AC:

1258202

AN:

1454964

Hom.:

545475

Cov.:

AF XY:

0.865

AC XY:

626288

AN XY:

724188

show subpopulations

African (AFR)

AF:

0.965

AC:

32214

AN:

33370

American (AMR)

AF:

0.735

AC:

32856

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.890

AC:

23217

AN:

26100

East Asian (EAS)

AF:

0.840

AC:

33313

AN:

39664

South Asian (SAS)

AF:

0.847

AC:

72914

AN:

86116

European-Finnish (FIN)

AF:

0.779

AC:

41555

AN:

53372

Middle Eastern (MID)

AF:

0.905

AC:

5201

AN:

5750

European-Non Finnish (NFE)

AF:

0.872

AC:

964311

AN:

1105728

Other (OTH)

AF:

0.875

AC:

52621

AN:

60146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

8548

17097

25645

34194

42742

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21144

42288

63432

84576

105720

<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:

0.880

AC:

133865

AN:

152180

Hom.:

59147

Cov.:

AF XY:

0.874

AC XY:

65025

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.960

AC:

39875

AN:

41536

American (AMR)

AF:

0.796

AC:

12154

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

3109

AN:

3472

East Asian (EAS)

AF:

0.861

AC:

4447

AN:

5166

South Asian (SAS)

AF:

0.852

AC:

4110

AN:

4826

European-Finnish (FIN)

AF:

0.769

AC:

8137

AN:

10576

Middle Eastern (MID)

AF:

0.918

AC:

270

AN:

294

European-Non Finnish (NFE)

AF:

0.869

AC:

59073

AN:

68006

Other (OTH)

AF:

0.877

AC:

1855

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

808

1616

2424

3232

4040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

900

1800

2700

3600

4500

<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:

0.872

Hom.:

229693

Bravo

AF:

0.886

TwinsUK

AF:

0.879

AC:

3261

ALSPAC

AF:

0.880

AC:

3391

ESP6500AA

AF:

0.956

AC:

4212

ESP6500EA

AF:

0.873

AC:

7505

ExAC

AF:

0.850

AC:

103217

Asia WGS

AF:

0.870

AC:

3024

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hawkinsinuria

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tyrosinemia type III;C2931042:Hawkinsinuria

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tyrosinemia type III

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.0033

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0000021

MetaSVM

Benign

-0.95

PhyloP100

4.2

PrimateAI

Uncertain

0.67

PROVEAN

Benign

3.8

REVEL

Benign

0.19

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.037

MPC

0.36

ClinPred

0.020

GERP RS

5.5

gMVP

0.29

Mutation Taster

=238/62

polymorphism (auto)

(source)

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

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