Genetic Variant HPDL:p.Arg72Ser (chr1-45327362-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032756.4(HPDL):c.214C>A(p.Arg72Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000436 in 1,582,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

HPDL
NM_032756.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.183

Variant links:

Genes affected

HPDL (HGNC:28242): (4-hydroxyphenylpyruvate dioxygenase like) The protein encoded by this intronless gene localizes to mitochondria, where it may function as 4-hydroxyphenylpyruvate dioxygenase. Clinical studies have identified several bi-allelic variants in this gene that lower the level of the encoded protein and lead to a clinically variable form of pediatric-onset spastic movement disorder. [provided by RefSeq, Aug 2020]

HPDL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08640081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPDL	NM_032756.4 link	c.214C>A	p.Arg72Ser	missense_variant	Exon 1 of 1	ENST00000334815.6	NP_116145.1	Q96IR7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPDL	ENST00000334815.6 link	c.214C>A	p.Arg72Ser	missense_variant	Exon 1 of 1	6	NM_032756.4	ENSP00000335060.3		Q96IR7

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000447

AC:

AN:

1430314

Hom.:

Cov.:

AF XY:

0.0000409

AC XY:

AN XY:

709656

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

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:

0.0000555

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.214C>A (p.R72S) alteration is located in exon 1 (coding exon 1) of the HPDL gene. This alteration results from a C to A substitution at nucleotide position 214, causing the arginine (R) at amino acid position 72 to be replaced by a serine (S). 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

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.0

DANN

Benign

0.84

DEOGEN2

Benign

0.096

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.31

M_CAP

Benign

0.036

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.81

REVEL

Benign

0.065

Sift

Benign

0.76

Sift4G

Benign

0.75

Polyphen

0.041

Vest4

0.20

MutPred

0.38

Gain of disorder (P = 0.0559);

MVP

0.70

MPC

0.63

ClinPred

0.028

GERP RS

1.9

Varity_R

0.084

gMVP

0.42

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