dbSNP rs896031772: SPR:p.Pro25Gln (chr2-72887506-C-A) – ACMG Classification: Uncertain_significance (3 pts)

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>A(p.Pro25Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPR
NM_003124.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.437

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:

ENSG00000309317 (HGNC:):

ENSG00000309317 links:

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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 10 pathogenic changes around while only 3 benign (77%) 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=0.119442075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPR	NM_003124.5 link	c.74C>A	p.Pro25Gln	missense_variant	Exon 1 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.74C>A	p.Pro25Gln	missense_variant	Exon 1 of 3	1	NM_003124.5	ENSP00000234454.5	P35270
SPR	ENST00000713723.1 link	c.74C>A	p.Pro25Gln	missense_variant	Exon 1 of 2			ENSP00000519027.1
SPR	ENST00000498749.2 link	n.74C>A		non_coding_transcript_exon_variant	Exon 1 of 3	3		ENSP00000519026.1
ENSG00000309317	ENST00000840248.1 link	n.51G>T		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1339382

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

660720

African (AFR)

AF:

0.00

AC:

AN:

27246

American (AMR)

AF:

0.00

AC:

AN:

29418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23634

East Asian (EAS)

AF:

0.00

AC:

AN:

29178

South Asian (SAS)

AF:

0.00

AC:

AN:

74628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1058642

Other (OTH)

AF:

0.00

AC:

AN:

55586

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.30

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-1.4

PhyloP100

-0.44

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.050

REVEL

Benign

0.17

Sift

Benign

0.65

Sift4G

Benign

0.59

Polyphen

0.0020

Vest4

0.18

MutPred

0.39

Gain of MoRF binding (P = 0.0309);

MVP

0.65

MPC

0.37

ClinPred

0.054

GERP RS

-3.2

PromoterAI

0.047

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.21

gMVP

0.46

Mutation Taster

=97/3

polymorphism

(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

LitVar

Below is the list of publications found by LitVar for variant 2:72887506 C>A . It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over