chr2-72887736-G-T

Variant names:

• chr2-72887736-G-T
• rs387907200
• NM_003124.5:c.304G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_003124.5(SPR):​c.304G>T​(p.Gly102Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000736 in 1,358,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/26 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G102G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: SPR NM_003124.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.04
• Publications: 5 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: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, G2P, Ambry Genetics
• BH4-deficient hyperphenylalaninemia A

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

ENSG00000309317 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a chain Sepiapterin reductase (size 260) in uniprot entity SPRE_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_003124.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.7325 (below the threshold of 3.09). Trascript score misZ: -0.70614 (below the threshold of 3.09). GenCC associations: The gene is linked to dopa-responsive dystonia due to sepiapterin reductase deficiency, BH4-deficient hyperphenylalaninemia A.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-72887736-G-T is Pathogenic according to our data. Variant chr2-72887736-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 31917.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPR	NM_003124.5	c.304G>T	p.Gly102Cys	missense_variant, splice_region_variant	Exon 1 of 3	ENST00000234454.6	NP_003115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPR	ENST00000234454.6	c.304G>T	p.Gly102Cys	missense_variant, splice_region_variant	Exon 1 of 3	1	NM_003124.5	ENSP00000234454.5
SPR	ENST00000713723.1	c.304G>T	p.Gly102Cys	missense_variant, splice_region_variant	Exon 1 of 2			ENSP00000519027.1
SPR	ENST00000498749.2	n.304G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	3		ENSP00000519026.1
ENSG00000309317	ENST00000840248.1	n.-180C>A		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.36e-7 AC: 1 AN: 1358884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 670482

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29260

American (AMR) AF: 0.00 AC: 0 AN: 32464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24182

East Asian (EAS) AF: 0.00 AC: 0 AN: 33426

South Asian (SAS) AF: 0.00 AC: 0 AN: 77280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1068430

Other (OTH) AF: 0.00 AC: 0 AN: 56470

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00192 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dopa-responsive dystonia due to sepiapterin reductase deficiency Pathogenic:1

Aug 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	37
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		8.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.85		Loss of disorder (P = 0.0556);
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		-0.30	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.96
gMVP		0.85
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.78		Position offset: 32

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

Other links and lift over

dbSNP: rs387907200; hg19: chr2-73114865;