5-140114873-T-G

Variant names:

• chr5-140114873-T-G
• rs1554129113
• NM_005859.5:c.692T>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005859.5(PURA):​c.692T>G​(p.Phe231Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F231S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PURA NM_005859.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.00
• Publications: 1 publications found

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]

MALINC1 (HGNC:49009): (mitosis associated long intergenic non-coding RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_005859.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-140114873-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 520768.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 5-140114873-T-G is Pathogenic according to our data. Variant chr5-140114873-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1335851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005859.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PURA	NM_005859.5	MANE Select	c.692T>G	p.Phe231Cys	missense	Exon 1 of 1	NP_005850.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PURA	ENST00000331327.5	TSL:6 MANE Select	c.692T>G	p.Phe231Cys	missense	Exon 1 of 1	ENSP00000332706.3
	PURA	ENST00000651386.1		c.692T>G	p.Phe231Cys	missense	Exon 2 of 2	ENSP00000499133.1
	MALINC1	ENST00000520928.2	TSL:3	n.-158A>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apparently de novo variant in a patient included in a cohort of individuals undergoing whole genome sequencing, however, clinical information was not provided (Stranneheim, et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33726816)

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PURA: PS2, PM2, PP2

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:1

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 231 of the PURA protein (p.Phe231Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PURA-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1335851). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PURA protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.94		Loss of stability (P = 0.0192)
MVP		0.86
MPC		4.1
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.90
gMVP		1.0
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs1554129113; hg19: chr5-139494458;