5-140114651-T-A

Variant names:

• chr5-140114651-T-A
• rs587782998
• NM_005859.5:c.470T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_005859.5(PURA):​c.470T>A​(p.Met157Lys) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M157V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PURA NM_005859.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.97
• Publications: 4 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr5-140114650-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1679405.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 5-140114651-T-A is Pathogenic according to our data. Variant chr5-140114651-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 156410.Status of the report is no_assertion_criteria_provided, 0 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.470T>A	p.Met157Lys	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.470T>A	p.Met157Lys	missense	Exon 1 of 1	ENSP00000332706.3
	PURA	ENST00000651386.1		c.470T>A	p.Met157Lys	missense	Exon 2 of 2	ENSP00000499133.1
	MALINC1	ENST00000520928.2	TSL:3	n.65A>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
PhyloP100		8.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.88
MutPred		0.68		Loss of stability (P = 0.0129)
MVP		0.73
MPC		3.5
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.91
gMVP		1.0
Mutation Taster		=2/98	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: rs587782998; hg19: chr5-139494236;