5-140114182-A-T

Variant names:

• chr5-140114182-A-T
• rs793888530
• NM_005859.5:c.1A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005859.5(PURA):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PURA NM_005859.5 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.78

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 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 104 codons. Genomic position: 140114491. Lost 0.320 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-140114182-A-T is Pathogenic according to our data. Variant chr5-140114182-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 192337.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.1A>T	p.Met1?	initiator_codon_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.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 1	6	NM_005859.5	ENSP00000332706.3
PURA	ENST00000651386.1	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 2			ENSP00000499133.1
PURA	ENST00000505703.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 2	3		ENSP00000498560.1
PURA	ENST00000502351.1	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 2	2		ENSP00000498760.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 8

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Aug 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.98	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.059	T
Polyphen		0.064	B
Vest4		0.51
MutPred		0.97		Loss of glycosylation at S6 (P = 0.2294);
MVP		0.81
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.81
gMVP		0.27

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: rs793888530; hg19: chr5-139493767;