NM_003124.5:c.355C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_003124.5(SPR):​c.355C>T​(p.Gln119*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

SPR
NM_003124.5 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.47

Publications

2 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: Pathogenic. The variant received 11 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-72888364-C-T is Pathogenic according to our data. Variant chr2-72888364-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12939.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPRNM_003124.5 linkc.355C>T p.Gln119* stop_gained Exon 2 of 3 ENST00000234454.6 NP_003115.1 P35270

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPRENST00000234454.6 linkc.355C>T p.Gln119* stop_gained Exon 2 of 3 1 NM_003124.5 ENSP00000234454.5 P35270
SPRENST00000713723.1 linkc.304+628C>T intron_variant Intron 1 of 1 ENSP00000519027.1
SPRENST00000498749.2 linkn.305-56C>T intron_variant Intron 1 of 2 3 ENSP00000519026.1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Dopa-responsive dystonia due to sepiapterin reductase deficiency Pathogenic:1
Aug 01, 2001
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.96
D
PhyloP100
6.5
Vest4
0.95
GERP RS
3.8
Mutation Taster
=4/196
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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: rs121917746; hg19: chr2-73115493; API