rs6730083

Variant names:

• chr2-72888868-G-A
• rs6730083
• NM_003124.5:c.595+264G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-72888868-G-A
• chr2-72888868-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003124.5(SPR):​c.595+264G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.836 in 152,200 control chromosomes in the GnomAD database, including 54,537 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.84 (54537 hom., cov: 32)
• Consequence: SPR NM_003124.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.297
• Publications: 4 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-72888868-G-A is Benign according to our data. Variant chr2-72888868-G-A is described in ClinVar as Benign. ClinVar VariationId is 1280180.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

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.595+264G>A		intron	N/A	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.595+264G>A		intron	N/A	ENSP00000234454.5	P35270
	SPR	ENST00000871611.1		c.595+264G>A		intron	N/A	ENSP00000541670.1
	SPR	ENST00000871609.1		c.571+264G>A		intron	N/A	ENSP00000541668.1

Frequencies

GnomAD3 genomes AF: 0.837 AC: 127256 AN: 152082 Hom.: 54529 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.895

Gnomad ASJ AF: 0.936

Gnomad EAS AF: 0.992

Gnomad SAS AF: 0.936

Gnomad FIN AF: 0.947

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.904

Gnomad OTH AF: 0.855

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.836 AC: 127290 AN: 152200 Hom.: 54537 Cov.: 32 AF XY: 0.842 AC XY: 62654 AN XY: 74420

African (AFR) AF: 0.633 AC: 26230 AN: 41458

American (AMR) AF: 0.895 AC: 13705 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.936 AC: 3251 AN: 3472

East Asian (EAS) AF: 0.992 AC: 5143 AN: 5182

South Asian (SAS) AF: 0.937 AC: 4523 AN: 4826

European-Finnish (FIN) AF: 0.947 AC: 10061 AN: 10626

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.904 AC: 61519 AN: 68016

Other (OTH) AF: 0.851 AC: 1794 AN: 2108

Alfa AF: 0.866 Hom.: 7193

Bravo AF: 0.822

Asia WGS AF: 0.924 AC: 3215 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.7
DANN	Benign	0.73
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs6730083;

hg19: chr2-73115997;