2-72887433-A-C

Position:

• chr2-72887433-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_003124.5(SPR):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000746 in 1,340,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: SPR NM_003124.5 initiator_codon
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.180

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_003124.5 (SPR) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-72887433-A-C is Pathogenic according to our data. Variant chr2-72887433-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1698420.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPR	NM_003124.5	c.1A>C	p.Met1?	initiator_codon_variant	1/3	ENST00000234454.6	NP_003115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPR	ENST00000234454.6	c.1A>C	p.Met1?	initiator_codon_variant	1/3	1	NM_003124.5	ENSP00000234454.5
SPR	ENST00000498749.1	n.52A>C		non_coding_transcript_exon_variant	1/3	3		ENSP00000519026.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.46e-7 AC: 1 AN: 1340942 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 662480

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: 9.44e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dopa-responsive dystonia due to sepiapterin reductase deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Neurology, Xijing Hospital, Fourth Military Medical University

Mar 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	12
DANN	Benign	0.74
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.80	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.24	T
Polyphen		0.010	B
Vest4		0.17
MutPred		0.99		Loss of sheet (P = 0.1907);
MVP		0.79
ClinPred		0.45	T
GERP RS		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.87
gMVP		0.55

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: chr2-73114562;