rs11833399

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.021 ( 94 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 101 hom. )

Consequence

HPD
NM_002150.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.96

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPD	NM_002150.3 linkuse as main transcript	c.338G>A	p.Arg113Gln	missense_variant	7/14	ENST00000289004.8
HPD	NM_001171993.2 linkuse as main transcript	c.221G>A	p.Arg74Gln	missense_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPD	ENST00000289004.8 linkuse as main transcript	c.338G>A	p.Arg113Gln	missense_variant	7/14	1	NM_002150.3	P1
HPD	ENST00000543163.5 linkuse as main transcript	c.221G>A	p.Arg74Gln	missense_variant	8/15	5			P32754-2
HPD	ENST00000542159.2 linkuse as main transcript	n.374G>A		non_coding_transcript_exon_variant	4/6	5

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3228

AN:

152122

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00712

AC:

1791

AN:

251492

Hom.:

AF XY:

0.00616

AC XY:

837

AN XY:

135922

show subpopulations

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 SAS exome

AF:

0.0108

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.:

AF XY:

0.00299

AC XY:

2176

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.0806

Gnomad4 AMR exome

AF:

0.00376

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0101

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.00593

GnomAD4 genome

AF:

0.0212

AC:

3231

AN:

152240

Hom.:

Cov.:

AF XY:

0.0202

AC XY:

1502

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0723

Gnomad4 AMR

AF:

0.00727

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0126

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.00432

Hom.:

Bravo

AF:

0.0246

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0713

AC:

314

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00860

AC:

1044

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hawkinsinuria

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 11, 2020

- -

Tyrosinemia type III;C2931042:Hawkinsinuria

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.45

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.068

T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.5

D;D

REVEL

Benign

0.076

Sift

Benign

0.20

T;T

Sift4G

Benign

0.21

T;T

Vest4

0.23

MVP

0.68

MPC

0.43

ClinPred

0.047

GERP RS

3.6

gMVP

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over