rs121917747

Variant names:

• chr2-72891502-A-G
• rs121917747
• NM_003124.5:c.751A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-72891502-A-G
• chr2-72891502-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1 PM2 PP2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.535
• Publications: 0 publications found

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)

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

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	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.3
DANN	Benign	0.94
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.63	N
PhyloP100		-0.54
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.23
Sift	Benign	0.79	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.066
MutPred		0.37		Loss of ubiquitination at K251 (P = 0.0141)
MVP		0.65
MPC		0.54
ClinPred		0.040	T
GERP RS		-4.3
Varity_R		0.12
gMVP		0.67
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs121917747; hg19: chr2-73118631;