2-72891502-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_003124.5(SPR):c.751A>T(p.Lys251*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SPR
NM_003124.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: -0.535

Publications

14 publications found

Variant links:

Genes affected

SPR (HGNC:11257): (sepiapterin reductase) This gene encodes an aldo-keto reductase that catalyzes the NADPH-dependent reduction of pteridine derivatives and is important in the biosynthesis of tetrahydrobiopterin (BH4). Mutations in this gene result in DOPA-responsive dystonia due to sepiaterin reductase deficiency. A pseudogene has been identified on chromosome 1. [provided by RefSeq, Jul 2008]

SPR Gene-Disease associations (from GenCC):

dopa-responsive dystonia due to sepiapterin reductase deficiency
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, G2P, Ambry Genetics
BH4-deficient hyperphenylalaninemia A
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

SPR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0445 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PP5

Variant 2-72891502-A-T is Pathogenic according to our data. Variant chr2-72891502-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003124.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPR	NM_003124.5	MANE Select	c.751A>T	p.Lys251*	stop_gained	Exon 3 of 3	NP_003115.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPR	ENST00000234454.6	TSL:1 MANE Select	c.751A>T	p.Lys251*	stop_gained	Exon 3 of 3	ENSP00000234454.5
SPR	ENST00000713723.1		c.460A>T	p.Lys154*	stop_gained	Exon 2 of 2	ENSP00000519027.1
SPR	ENST00000498749.2	TSL:3	n.*333A>T		non_coding_transcript_exon	Exon 3 of 3	ENSP00000519026.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000795

AC:

AN:

251488

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000149

AC:

218

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

113

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000183

AC:

203

AN:

1112012

Other (OTH)

AF:

0.000116

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

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:

0.0000847

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dopa-responsive dystonia due to sepiapterin reductase deficiency

Pathogenic:5

May 25, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jul 18, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

May 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21431957). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 21677200) and co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18502672, 21677200). It has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012944 / PMID: 16917893). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

not provided

Pathogenic:3

Nov 19, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect, with less than 1% residual SPR enzyme activity on western blot analysis (Arrabal et al., 2011); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 11 amino acids are lost (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21677200, 24212389, 22522443, 21431957, 16917893, 25763508, 31589614)

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPR: PM3:Strong, PVS1:Strong, PM2:Supporting, PP1, PS3:Supporting

Aug 13, 2022

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

DNA sequence analysis of the SPR gene demonstrated a sequence change, c.751A>T, which results in the creation of a premature stop codon at amino acid position 251, p.Lys251*. While this sequence change is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acids of the SPR protein. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the European subpopulation (dbSNP rs121917747). This sequence change has previously been described in individuals with SPR deficiency in both homozygous and the compound heterozygous state (PMID: 21431957,18502672, 25763508,16917893, 24212389) . Functional assay involving western blot analysis showed significantly reduced residual SPR enzyme activity for this sequence change (PMID: 21431957). These collective evidences indicate that this sequence change is pathogenic.

Dystonic disorder

Pathogenic:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Lys251*) in the SPR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the SPR protein. This variant is present in population databases (rs121917747, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with SPR-related conditions (PMID: 16917893, 18502672, 21431957, 21677200, 24212389, 25763508, 29116116). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12944). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Benign

-0.050

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.097

PhyloP100

-0.54

Vest4

0.60

GERP RS

-4.3

Mutation Taster

=20/180

disease causing (ClinVar)

(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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over