2-72891390-C-A

Variant names:

• chr2-72891390-C-A
• NM_003124.5:c.639C>A
• SPR p.Ser213Ser

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003124.5(SPR):​c.639C>A​(p.Ser213Ser) variant causes a synonymous 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. Synonymous variant affecting the same amino acid position (i.e. S213S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPR NM_003124.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.33
• Publications: 0 publications found

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]

SPR Gene-Disease associations (from GenCC):

• dopa-responsive dystonia due to sepiapterin reductase deficiency

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

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP7: Synonymous conserved (PhyloP=-5.33 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003124.5. 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.639C>A	p.Ser213Ser	synonymous	Exon 3 of 3	NP_003115.1	P35270

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPR	ENST00000234454.6	TSL:1 MANE Select	c.639C>A	p.Ser213Ser	synonymous	Exon 3 of 3	ENSP00000234454.5	P35270
	SPR	ENST00000871611.1		c.624C>A	p.Ser208Ser	synonymous	Exon 3 of 3	ENSP00000541670.1
	SPR	ENST00000871609.1		c.615C>A	p.Ser205Ser	synonymous	Exon 3 of 3	ENSP00000541668.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.15
DANN	Benign	0.51
PhyloP100		-5.3
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-73118519;