chr5-140114486-T-G

Variant names:

• chr5-140114486-T-G
• rs793888531
• NM_005859.5:c.305T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_005859.5(PURA):​c.305T>G​(p.Leu102Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PURA NM_005859.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.06

Genes affected

PURA (HGNC:9701): (purine rich element binding protein A) This gene product is a sequence-specific, single-stranded DNA-binding protein. It binds preferentially to the single strand of the purine-rich element termed PUR, which is present at origins of replication and in gene flanking regions in a variety of eukaryotes from yeasts through humans. Thus, it is implicated in the control of both DNA replication and transcription. Deletion of this gene has been associated with myelodysplastic syndrome and acute myelogenous leukemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PURA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 3.3704 (above the threshold of 3.09). Trascript score misZ: 4.4395 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation, complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 5-140114486-T-G is Pathogenic according to our data. Variant chr5-140114486-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 192338.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PURA	NM_005859.5	c.305T>G	p.Leu102Arg	missense_variant	Exon 1 of 1	ENST00000331327.5	NP_005850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PURA	ENST00000331327.5	c.305T>G	p.Leu102Arg	missense_variant	Exon 1 of 1	6	NM_005859.5	ENSP00000332706.3
PURA	ENST00000651386.1	c.305T>G	p.Leu102Arg	missense_variant	Exon 2 of 2			ENSP00000499133.1
PURA	ENST00000505703.2	c.305T>G	p.Leu102Arg	missense_variant	Exon 2 of 2	3		ENSP00000498560.1
PURA	ENST00000502351.1	c.*226T>G		downstream_gene_variant		2		ENSP00000498760.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 03, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Leu102Arg (CTC>CGC): c.305 T>G in exon 1 in the PURA gene (NM_005859.4). The L102R variant in the PURA gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The L102R variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. This change occurs at a residue that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The L102R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret L102R as a disease-causing mutation. The variant has been observed de novo with confirmed parentage. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.84		Gain of MoRF binding (P = 0.0071);
MVP		0.86
MPC		4.1
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		1.0

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: rs793888531; hg19: chr5-139494071;