Genetic Variant NM_003124.5:c.751A>G (chr2-72891502-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1PM2PP2BP4_Strong

The NM_003124.5(SPR):c.751A>G(p.Lys251Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SPR
NM_003124.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.535

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: Uncertain_significance. The variant received 1 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=0.030985773).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003124.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPR	NM_003124.5	MANE Select	c.751A>G	p.Lys251Glu	missense	Exon 3 of 3	NP_003115.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPR	ENST00000234454.6	TSL:1 MANE Select	c.751A>G	p.Lys251Glu	missense	Exon 3 of 3	ENSP00000234454.5
SPR	ENST00000713723.1		c.460A>G	p.Lys154Glu	missense	Exon 2 of 2	ENSP00000519027.1
SPR	ENST00000498749.2	TSL:3	n.*333A>G		non_coding_transcript_exon	Exon 3 of 3	ENSP00000519026.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

5.3

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.19

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.49

M_CAP

Benign

0.043

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.63

PhyloP100

-0.54

PrimateAI

Benign

0.23

PROVEAN

Benign

0.22

REVEL

Benign

0.23

Sift

Benign

0.79

Sift4G

Benign

0.74

Polyphen

0.0

Vest4

0.066

MutPred

0.37

Loss of ubiquitination at K251 (P = 0.0141)

MVP

0.65

MPC

0.54

ClinPred

0.040

GERP RS

-4.3

Varity_R

0.12

gMVP

0.67

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over