Variant 12-121856362-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002150.3(HPD):c.286A>G(p.Ile96Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HPD
NM_002150.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.223

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15456873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HPD	NM_002150.3 linkuse as main transcript	c.286A>G	p.Ile96Val	missense_variant	6/14	ENST00000289004.8	NP_002141.2
LOC105370035	XR_002957437.2 linkuse as main transcript	n.110T>C		non_coding_transcript_exon_variant	1/3
HPD	NM_001171993.2 linkuse as main transcript	c.169A>G	p.Ile57Val	missense_variant	8/16		NP_001165464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPD	ENST00000289004.8 linkuse as main transcript	c.286A>G	p.Ile96Val	missense_variant	6/14	1	NM_002150.3	ENSP00000289004	P1
	ENST00000543848.1 linkuse as main transcript	n.104T>C		non_coding_transcript_exon_variant	1/3	3
HPD	ENST00000543163.5 linkuse as main transcript	c.169A>G	p.Ile57Val	missense_variant	7/15	5		ENSP00000441677		P32754-2
HPD	ENST00000542159.2 linkuse as main transcript	n.322A>G		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000121

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2021

The c.286A>G (p.I96V) alteration is located in exon 6 (coding exon 6) of the HPD gene. This alteration results from a A to G substitution at nucleotide position 286, causing the isoleucine (I) at amino acid position 96 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.0038

T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.93

D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

0.0

N;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;T

Sift4G

Benign

0.93

T;T

Vest4

0.27

MutPred

0.62

Gain of catalytic residue at F98 (P = 0.0534);.;

MVP

0.38

MPC

0.31

ClinPred

0.16

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.39

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