NM_003124.5:c.74C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_003124.5(SPR):​c.74C>T​(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000224 in 1,339,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. P25R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

SPR
NM_003124.5 missense

Scores

1
1
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.437

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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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;
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.113752574).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPRNM_003124.5 linkc.74C>T p.Pro25Leu missense_variant Exon 1 of 3 ENST00000234454.6 NP_003115.1 P35270

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPRENST00000234454.6 linkc.74C>T p.Pro25Leu missense_variant Exon 1 of 3 1 NM_003124.5 ENSP00000234454.5 P35270
SPRENST00000713723.1 linkc.74C>T p.Pro25Leu missense_variant Exon 1 of 2 ENSP00000519027.1
SPRENST00000498749.2 linkn.74C>T non_coding_transcript_exon_variant Exon 1 of 3 3 ENSP00000519026.1
ENSG00000309317ENST00000840248.1 linkn.51G>A non_coding_transcript_exon_variant Exon 1 of 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000224
AC:
3
AN:
1339382
Hom.:
0
Cov.:
31
AF XY:
0.00000454
AC XY:
3
AN XY:
660720
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
27246
American (AMR)
AF:
0.00
AC:
0
AN:
29418
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23634
East Asian (EAS)
AF:
0.00
AC:
0
AN:
29178
South Asian (SAS)
AF:
0.0000134
AC:
1
AN:
74628
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
36916
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4134
European-Non Finnish (NFE)
AF:
0.00000189
AC:
2
AN:
1058642
Other (OTH)
AF:
0.00
AC:
0
AN:
55586
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
8.1
DANN
Benign
0.92
DEOGEN2
Benign
0.29
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.022
N
LIST_S2
Benign
0.67
T
M_CAP
Pathogenic
0.38
D
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
-2.5
N
PhyloP100
-0.44
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
0.13
N
REVEL
Benign
0.19
Sift
Benign
0.59
T
Sift4G
Benign
0.35
T
Polyphen
0.0020
B
Vest4
0.11
MutPred
0.44
Loss of disorder (P = 0.0659);
MVP
0.70
MPC
0.39
ClinPred
0.18
T
GERP RS
-3.2
PromoterAI
0.12
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.22
gMVP
0.57
Mutation Taster
=95/5
polymorphism

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

Other links and lift over

dbSNP: rs896031772; hg19: chr2-73114635; API