2-72887223-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000840248.1(ENSG00000309317):​n.164+170T>A variant causes a intron 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000309317 ENST00000840248.1 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

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>T		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>A		intron	N/A
	SPR	ENST00000234454.6	TSL:1 MANE Select	c.-210A>T		upstream_gene	N/A	ENSP00000234454.5	P35270
	SPR	ENST00000871611.1		c.-210A>T		upstream_gene	N/A	ENSP00000541670.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 311242 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 158646

African (AFR) AF: 0.00 AC: 0 AN: 7182

American (AMR) AF: 0.00 AC: 0 AN: 6698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9018

East Asian (EAS) AF: 0.00 AC: 0 AN: 20872

South Asian (SAS) AF: 0.00 AC: 0 AN: 10304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1416

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 214834

Other (OTH) AF: 0.00 AC: 0 AN: 18270

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 7081

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.50
DANN	Benign	0.52
PhyloP100		-6.0
PromoterAI		0.38	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;