2-72888457-A-G

Position:

chr2-72888457-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_003124.5(SPR):c.448A>G(p.Arg150Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000855 in 1,613,918 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: 0.000088 ( 0 hom. )

Consequence

SPR
NM_003124.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.95

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

PP5

Variant 2-72888457-A-G is Pathogenic according to our data. Variant chr2-72888457-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPR	NM_003124.5 linkuse as main transcript	c.448A>G	p.Arg150Gly	missense_variant	2/3	ENST00000234454.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPR	ENST00000234454.6 linkuse as main transcript	c.448A>G	p.Arg150Gly	missense_variant	2/3	1	NM_003124.5	P1
SPR	ENST00000498749.1 linkuse as main transcript	n.393A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251238

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000883

AC:

129

AN:

1461724

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000246

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:

0.0000953

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000428

Hom.:

Bravo

AF:

0.0000567

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000576

AC:

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

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 27, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 12, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Aug 04, 2022	This sequence change in SPR is predicted to replace arginine with glycine at codon 150, p.(Arg150Gly). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in a beta-strand. There is a large physicochemical difference between arginine and glycine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (7/35,402 alleles) in the Latino/admixed American population, which is consistent with a recessive condition. This variant has been detected in at least ten individuals with sepiapterin reductase deficiency. Of those individuals, two individuals were homozygous and 8 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and one of those was confirmed in trans by parental testing (PMID: 11443547, 17159114, 19491146, 22522443). The variant demonstrates deficient enzyme activity in an in vitro functional assay (PMID: 11443547). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Supporting, PM2_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 15, 2019	Variant summary: SPR c.448A>G (p.Arg150Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251238 control chromosomes (gnomAD). The variant, c.448A>G, has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Sepiapterin reductase deficiency (e.g. Bonafe_2001, Clot_2009, Friedman_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication, Bonafe_2001, reported that the variant almost completely abolished the enzyme activity. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2023	Published functional studies demonstrate absent sepiapterin reductase enzyme activity in vitro (Bonafe et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24212389, 16917893, 19491146, 28516087, 21677200, 11443547, 17159114, 27080360, 26123188, 23430877, 22522443, 21431957, 33977029, 30799092, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -

SPR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

The SPR c.448A>G variant is predicted to result in the amino acid substitution p.Arg150Gly. This variant has been reported to be causative for dopa-responsive dystonia due to sepiapterin reductase deficiency (Bonafé et al. 2001. PubMed ID: 11443547; Leuzzi et al. 2013. PubMed ID: 24212389; Thibert et al. 2012. PubMed ID: 23430877). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Dystonic disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 150 of the SPR protein (p.Arg150Gly). This variant is present in population databases (rs104893665, gnomAD 0.02%). This missense change has been observed in individual(s) with sepiapterin reductase deficiency (PMID: 11443547, 21431957, 21677200, 23430877, 24212389). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12941). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SPR function (PMID: 11443547). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Benign

-0.0085

Eigen_PC

Benign

-0.027

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

-0.31

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.73

MVP

0.92

MPC

1.4

ClinPred

0.75

GERP RS

3.1

Varity_R

0.87

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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