rs1876487

Variant names:

• chr2-72887223-A-C
• rs1876487
• ENST00000840248.1:n.164+170T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-72887223-A-C
• chr2-72887223-A-G
• chr2-72887223-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000840248.1(ENSG00000309317):​n.164+170T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 462,886 control chromosomes in the GnomAD database, including 107,537 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (28196 hom., cov: 33)
  • Exomes 𝑓: 0.70 (79341 hom.)
• Consequence: ENSG00000309317 ENST00000840248.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.97
• Publications: 18 publications found

Genes affected

ENSG00000309317 (HGNC:):

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: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, PanelApp Australia, Genomics England PanelApp, ClinGen, Orphanet
• BH4-deficient hyperphenylalaninemia A

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-72887223-A-C is Benign according to our data. Variant chr2-72887223-A-C is described in ClinVar as Benign. ClinVar VariationId is 1167479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000840248.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPR	NM_003124.5	MANE Select	c.-210A>C		upstream_gene	N/A	NP_003115.1	P35270

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000309317	ENST00000840248.1		n.164+170T>G		intron	N/A
	SPR	ENST00000234454.6	TSL:1 MANE Select	c.-210A>C		upstream_gene	N/A	ENSP00000234454.5	P35270
	SPR	ENST00000871611.1		c.-210A>C		upstream_gene	N/A	ENSP00000541670.1

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83872 AN: 151992 Hom.: 28209 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.730

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.587

GnomAD4 exome AF: 0.704 AC: 218778 AN: 310778 Hom.: 79341 AF XY: 0.709 AC XY: 112273 AN XY: 158430

African (AFR) AF: 0.147 AC: 1058 AN: 7178

American (AMR) AF: 0.607 AC: 4060 AN: 6688

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 6848 AN: 9012

East Asian (EAS) AF: 0.932 AC: 19442 AN: 20868

South Asian (SAS) AF: 0.839 AC: 8621 AN: 10274

European-Finnish (FIN) AF: 0.717 AC: 16213 AN: 22612

Middle Eastern (MID) AF: 0.722 AC: 1021 AN: 1414

European-Non Finnish (NFE) AF: 0.696 AC: 149224 AN: 214496

Other (OTH) AF: 0.674 AC: 12291 AN: 18236

GnomAD4 genome AF: 0.551 AC: 83861 AN: 152108 Hom.: 28196 Cov.: 33 AF XY: 0.562 AC XY: 41778 AN XY: 74346

African (AFR) AF: 0.149 AC: 6180 AN: 41542

American (AMR) AF: 0.590 AC: 9022 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2650 AN: 3472

East Asian (EAS) AF: 0.934 AC: 4778 AN: 5114

South Asian (SAS) AF: 0.853 AC: 4113 AN: 4824

European-Finnish (FIN) AF: 0.730 AC: 7730 AN: 10590

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.697 AC: 47364 AN: 67954

Other (OTH) AF: 0.586 AC: 1238 AN: 2112

Alfa AF: 0.583 Hom.: 7081

Bravo AF: 0.521

Asia WGS AF: 0.820 AC: 2851 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dystonic disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.54
DANN	Benign	0.43
PhyloP100		-6.0
PromoterAI		-0.087	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1876487; hg19: chr2-73114352; COSMIC: COSV52298477;