2-72888532-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_003124.5(SPR):c.523G>T(p.Ala175Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A175D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SPR
NM_003124.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.56

Publications

0 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 11 ACMG points.

PM1

In a chain Sepiapterin reductase (size 260) in uniprot entity SPRE_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_003124.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-72888533-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 807499.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.7325 (below the threshold of 3.09). Trascript score misZ: -0.70614 (below the threshold of 3.09). GenCC associations: The gene is linked to dopa-responsive dystonia due to sepiapterin reductase deficiency, BH4-deficient hyperphenylalaninemia A.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPR	NM_003124.5 link	c.523G>T	p.Ala175Ser	missense_variant	Exon 2 of 3	ENST00000234454.6	NP_003115.1	P35270

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPR	ENST00000234454.6 link	c.523G>T	p.Ala175Ser	missense_variant	Exon 2 of 3	1	NM_003124.5	ENSP00000234454.5	P35270
SPR	ENST00000498749.2 link	n.*105G>T		non_coding_transcript_exon_variant	Exon 2 of 3	3		ENSP00000519026.1
SPR	ENST00000498749.2 link	n.*105G>T		3_prime_UTR_variant	Exon 2 of 3	3		ENSP00000519026.1
SPR	ENST00000713723.1 link	c.304+796G>T		intron_variant	Intron 1 of 1			ENSP00000519027.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452362

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33240

American (AMR)

AF:

0.00

AC:

AN:

43828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25506

East Asian (EAS)

AF:

0.00

AC:

AN:

39550

South Asian (SAS)

AF:

0.00

AC:

AN:

84934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106622

Other (OTH)

AF:

0.00

AC:

AN:

59872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.5

PhyloP100

9.6

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.75

MutPred

0.88

Loss of methylation at R177 (P = 0.0751);

MVP

0.96

MPC

1.1

ClinPred

1.0

GERP RS

4.7

Varity_R

0.93

gMVP

0.85

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over