2-72887544-G-C

Variant names:

• chr2-72887544-G-C
• NM_003124.5:c.112G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003124.5(SPR):​c.112G>C​(p.Val38Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000761 in 1,314,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. V38I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: SPR NM_003124.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33193833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPR	NM_003124.5	c.112G>C	p.Val38Leu	missense_variant	Exon 1 of 3	ENST00000234454.6	NP_003115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPR	ENST00000234454.6	c.112G>C	p.Val38Leu	missense_variant	Exon 1 of 3	1	NM_003124.5	ENSP00000234454.5
SPR	ENST00000498749.1	n.163G>C		non_coding_transcript_exon_variant	Exon 1 of 3	3		ENSP00000519026.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1314204 Hom.: 0 Cov.: 31 AF XY: 0.00000154 AC XY: 1 AN XY: 647538

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.54e-7

Gnomad4 OTH exome AF: 0.00

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	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.74
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.89	L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Benign	0.43	T
Sift4G	Benign	0.42	T
Polyphen		0.028	B
Vest4		0.17
MutPred		0.52		Loss of catalytic residue at V38 (P = 0.0674);
MVP		0.93
MPC		0.41
ClinPred		0.16	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.53
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-73114673;