rs35849100

Positions:

chr12-121858702-A-C

Variant summary

Our verdict is Benign. Variant got -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. 13/18 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

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:

HPD (HGNC:):

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=0.0028541684).

BP6

Variant 12-121858702-A-C is Benign according to our data. Variant chr12-121858702-A-C is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	Protein	UniProt
HPD	NM_002150.3 linkuse as main transcript	c.15T>G	p.Ser5Arg	missense_variant	2/14	ENST00000289004.8	NP_002141.2	P32754
HPD	NM_001171993.2 linkuse as main transcript	c.-103T>G		5_prime_UTR_variant	4/16		NP_001165464.1	P32754-2
LOC105370035	XR_002957437.2 linkuse as main transcript	n.614+864A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HPD	ENST00000289004.8 linkuse as main transcript	c.15T>G	p.Ser5Arg	missense_variant	2/14	1	NM_002150.3	ENSP00000289004.4	A0A0B4J1R4
HPD	ENST00000543163.5 linkuse as main transcript	c.-103T>G		5_prime_UTR_variant	3/15	5		ENSP00000441677.1	P32754-2
HPD	ENST00000535114.1 linkuse as main transcript	n.47T>G		non_coding_transcript_exon_variant	2/4	4

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

GnomAD3 exomes

AF:

0.0142

AC:

3560

AN:

251476

Hom.:

113

AF XY:

0.0121

AC XY:

1642

AN XY:

135914

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 SAS exome

AF:

0.00882

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

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.0670

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00955

Gnomad4 FIN exome

AF:

0.00154

Gnomad4 NFE exome

AF:

0.00386

Gnomad4 OTH exome

AF:

0.00546

GnomAD4 genome

AF:

0.00659

AC:

1003

AN:

152124

Hom.:

Cov.:

AF XY:

0.00678

AC XY:

504

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00116

Gnomad4 AMR

AF:

0.0301

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0104

Gnomad4 FIN

AF:

0.00161

Gnomad4 NFE

AF:

0.00585

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.00678

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

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 17, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2021	- -

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

Tyrosinemia type III;C2931042:Hawkinsinuria

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

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

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

gMVP

0.29

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

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