5-140114480-T-C

Variant names:

• chr5-140114480-T-C
• rs587782995
• NM_005859.5:c.299T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_005859.5(PURA):​c.299T>C​(p.Leu100Pro) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L100L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PURA NM_005859.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.99
• Publications: 7 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 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_005859.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 5-140114480-T-C is Pathogenic according to our data. Variant chr5-140114480-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 156407.Status of the report is criteria_provided_single_submitter, 1 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.299T>C	p.Leu100Pro	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.299T>C	p.Leu100Pro	missense	Exon 1 of 1	ENSP00000332706.3
	PURA	ENST00000651386.1		c.299T>C	p.Leu100Pro	missense	Exon 2 of 2	ENSP00000499133.1
	PURA	ENST00000505703.2	TSL:3	c.299T>C	p.Leu100Pro	missense	Exon 2 of 2	ENSP00000498560.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:2

Aug 05, 2017

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 06, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Seizure;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C2267233:Neonatal hypotonia;C3714756:Intellectual disability Pathogenic:1

Sep 15, 2014

Whole genome laboratory; Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.83		Loss of stability (P = 0.0016)
MVP		0.88
MPC		4.3
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		-0.0090	Neutral
Varity_R		0.97
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs587782995; hg19: chr5-139494065;