chr2-72891405-G-T

Variant names:

• chr2-72891405-G-T
• rs150078285
• NM_003124.5:c.654G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003124.5(SPR):​c.654G>T​(p.Met218Ile) 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. 15/21 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. M218T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPR NM_003124.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00100

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105505794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPR	NM_003124.5	c.654G>T	p.Met218Ile	missense_variant	Exon 3 of 3	ENST00000234454.6	NP_003115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPR	ENST00000234454.6	c.654G>T	p.Met218Ile	missense_variant	Exon 3 of 3	1	NM_003124.5	ENSP00000234454.5
SPR	ENST00000498749.1	n.599G>T		non_coding_transcript_exon_variant	Exon 3 of 3	3		ENSP00000519026.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.8
DANN	Benign	0.81
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.10	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.20
Sift	Benign	0.31	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.39		Loss of catalytic residue at V214 (P = 0.0201);
MVP		0.77
MPC		0.42
ClinPred		0.042	T
GERP RS		-2.0
Varity_R		0.13
gMVP		0.41

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

Other links and lift over

dbSNP: rs150078285; hg19: chr2-73118534;