rs36023382

chr12-121839985-C-Achr12-121839985-C-Gchr12-121839985-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/18 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 0.013 ( 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:4

Conservation

PhyloP100: 1.13

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=0.0036437213).

BP6

Variant 12-121839985-C-A is Benign according to our data. Variant chr12-121839985-C-A is described in ClinVar as [Benign]. Clinvar id is 307478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-121839985-C-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPD	NM_002150.3 linkuse as main transcript	c.1018G>T	p.Val340Leu	missense_variant	13/14	ENST00000289004.8
HPD	NM_001171993.2 linkuse as main transcript	c.901G>T	p.Val301Leu	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPD	ENST00000289004.8 linkuse as main transcript	c.1018G>T	p.Val340Leu	missense_variant	13/14	1	NM_002150.3	P1
HPD	ENST00000543163.5 linkuse as main transcript	c.901G>T	p.Val301Leu	missense_variant	14/15	5			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

GnomAD3 exomes

AF:

0.0140

AC:

3528

AN:

251486

Hom.:

AF XY:

0.0145

AC XY:

1965

AN XY:

135916

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 SAS exome

AF:

0.0261

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

Gnomad4 AFR exome

AF:

0.0201

Gnomad4 AMR exome

AF:

0.0114

Gnomad4 ASJ exome

AF:

0.0650

Gnomad4 EAS exome

AF:

0.0160

Gnomad4 SAS exome

AF:

0.0230

Gnomad4 FIN exome

AF:

0.0146

Gnomad4 NFE exome

AF:

0.00445

Gnomad4 OTH exome

AF:

0.0141

GnomAD4 genome

AF:

0.0127

AC:

1924

AN:

151932

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

982

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.0183

Gnomad4 AMR

AF:

0.0117

Gnomad4 ASJ

AF:

0.0686

Gnomad4 EAS

AF:

0.0181

Gnomad4 SAS

AF:

0.0231

Gnomad4 FIN

AF:

0.0153

Gnomad4 NFE

AF:

0.00493

Gnomad4 OTH

AF:

0.0190

Alfa

AF:

0.0104

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: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 12, 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 12, 2018

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 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

0.16

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

Cadd

Benign

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

MutationTaster

Benign

0.99

D;D

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

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

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