rs786204835

Variant names:

• chr5-140114870-GCTT-G
• rs786204835
• NM_005859.5:c.697_699delTTC

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_005859.5(PURA):​c.697_699delTTC​(p.Phe233del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003921115: The Phe233del variant in PURA has been reported in 8 patients with autosomal dominat PURA syndrome, characterized by moderate to severe intellectual disability (ID) and several early-onset issues including motor delay, hypotonia, feeding difficulties, hyperthermia, hypersomnolence, hypoventilation/apneas, speech delay and abnormal nonepileptic movements. p.Phe233del falls in the third PUR domain that mediate dimerization, and is predicted to cause local folding defects (Reijnders MRF et al., 2018 and Hunt D et al., 2014).". Synonymous variant affecting the same amino acid position (i.e. F233F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PURA NM_005859.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 8.00
• Publications: 14 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003921115: The Phe233del variant in PURA has been reported in 8 patients with autosomal dominat PURA syndrome, characterized by moderate to severe intellectual disability (ID) and several early-onset issues including motor delay, hypotonia, feeding difficulties, hyperthermia, hypersomnolence, hypoventilation/apneas, speech delay and abnormal nonepileptic movements. p.Phe233del falls in the third PUR domain that mediate dimerization, and is predicted to cause local folding defects (Reijnders MRF et al., 2018 and Hunt D et al., 2014).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_005859.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005859.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 5-140114870-GCTT-G is Pathogenic according to our data. Variant chr5-140114870-GCTT-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 189319.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PURA	NM_005859.5	MANE Select	c.697_699delTTC	p.Phe233del	conservative_inframe_deletion	Exon 1 of 1	NP_005850.1	Q00577

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PURA	ENST00000331327.5	TSL:6 MANE Select	c.697_699delTTC	p.Phe233del	conservative_inframe_deletion	Exon 1 of 1	ENSP00000332706.3	Q00577
	PURA	ENST00000651386.1		c.697_699delTTC	p.Phe233del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000499133.1	Q00577
	MALINC1	ENST00000520928.2	TSL:3	n.-158_-156delAAG		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome (10)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	PURA Syndrome (1)
1	-	-	PURA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=8/92	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: rs786204835; hg19: chr5-139494455;