chr1-45327282-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS2

The NM_032756.4(HPDL):c.134T>A(p.Leu45Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00202 in 1,593,358 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

HPDL
NM_032756.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 4.62

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

HPDL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_032756.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 0.93302 (below the threshold of 3.09). Trascript score misZ: -1.2259 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities.

BP4

Computational evidence support a benign effect (MetaRNN=0.0148971975).

BP6

Variant 1-45327282-T-A is Benign according to our data. Variant chr1-45327282-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1683729.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032756.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPDL	NM_032756.4	MANE Select	c.134T>A	p.Leu45Gln	missense	Exon 1 of 1	NP_116145.1	Q96IR7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPDL	ENST00000334815.6	TSL:6 MANE Select	c.134T>A	p.Leu45Gln	missense	Exon 1 of 1	ENSP00000335060.3	Q96IR7

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

225

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00267

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00139

AC:

292

AN:

209650

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.000161

Gnomad AMR exome

AF:

0.000774

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000393

Gnomad NFE exome

AF:

0.00266

Gnomad OTH exome

AF:

0.00152

GnomAD4 exome

AF:

0.00208

AC:

2997

AN:

1441014

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1404

AN XY:

715746

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

33106

American (AMR)

AF:

0.000735

AC:

AN:

42198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25604

East Asian (EAS)

AF:

0.00

AC:

AN:

38938

South Asian (SAS)

AF:

0.000249

AC:

AN:

84270

European-Finnish (FIN)

AF:

0.00105

AC:

AN:

47396

Middle Eastern (MID)

AF:

0.000871

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00253

AC:

2797

AN:

1104240

Other (OTH)

AF:

0.00136

AC:

AN:

59520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

199

398

596

795

994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152344

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41588

American (AMR)

AF:

0.00105

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00268

AC:

182

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00165

AC:

ExAC

AF:

0.00137

AC:

164

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

HPDL-related disorder (1)

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.15

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.57

M_CAP

Benign

0.070

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.71

MutationAssessor

Benign

2.0

PhyloP100

4.6

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Benign

0.040

Sift4G

Uncertain

0.0080

Polyphen

0.024

Vest4

0.38

MVP

0.69

MPC

0.60

ClinPred

0.083

GERP RS

3.9

PromoterAI

-0.042

Neutral

(source)

Varity_R

0.30

gMVP

0.88

Mutation Taster

=58/42

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over