rs146099322

chr2-72887544-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003124.5(SPR):c.112G>A(p.Val38Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00591 in 1,466,384 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (33 hom.)
• Consequence: SPR NM_003124.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.35

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010404646).
• BP6: Variant 2-72887544-G-A is Benign according to our data. Variant chr2-72887544-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239509.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=3, Uncertain_significance=1}. Variant chr2-72887544-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00511 (778/152188) while in subpopulation AMR AF= 0.00941 (144/15296). AF 95% confidence interval is 0.00816. There are 4 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPR	NM_003124.5	c.112G>A	p.Val38Ile	missense_variant	1/3	ENST00000234454.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPR	ENST00000234454.6	c.112G>A	p.Val38Ile	missense_variant	1/3	1	NM_003124.5	P1
SPR	ENST00000498749.1	n.163G>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 778 AN: 152080 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00416

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00759

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00387 AC: 283 AN: 73058 Hom.: 0 AF XY: 0.00347 AC XY: 146 AN XY: 42086

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00331

Gnomad ASJ exome AF: 0.00289

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000340

Gnomad FIN exome AF: 0.00378

Gnomad NFE exome AF: 0.00689

Gnomad OTH exome AF: 0.00438

GnomAD4 exome AF: 0.00601 AC: 7894 AN: 1314196 Hom.: 33 Cov.: 31 AF XY: 0.00587 AC XY: 3800 AN XY: 647536

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.00311

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000538

Gnomad4 FIN exome AF: 0.00350

Gnomad4 NFE exome AF: 0.00695

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.00511 AC: 778 AN: 152188 Hom.: 4 Cov.: 33 AF XY: 0.00496 AC XY: 369 AN XY: 74418

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00416

Gnomad4 NFE AF: 0.00759

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00535 Hom.: 1

Bravo AF: 0.00460

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00158 AC: 6

ESP6500EA AF: 0.00491 AC: 37

ExAC AF: 0.00171 AC: 169

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SPR: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	This variant is associated with the following publications: (PMID: 25957637) -

Dopa-responsive dystonia due to sepiapterin reductase deficiency Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Department of Neurology, Xijing Hospital, Fourth Military Medical University	Mar 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 13, 2016

- -

SPR-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Dystonic disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.20
Sift	Uncertain	0.026	D
Sift4G	Benign	0.19	T
Polyphen		0.051	B
Vest4		0.12
MVP		0.84
MPC		0.42
ClinPred		0.029	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.19
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs146099322; hg19: chr2-73114673;