rs1554129019

Positions:

• chr5-140114263-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005859.5(PURA):​c.82T>C​(p.Ser28Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PURA NM_005859.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0520

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PURA. . Gene score misZ 3.3704 (greater than the threshold 3.09). Trascript score misZ 4.4395 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24570984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PURA	NM_005859.5	c.82T>C	p.Ser28Pro	missense_variant	1/1	ENST00000331327.5	NP_005850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PURA	ENST00000331327.5	c.82T>C	p.Ser28Pro	missense_variant	1/1		NM_005859.5	ENSP00000332706	P1
PURA	ENST00000651386.1	c.82T>C	p.Ser28Pro	missense_variant	2/2			ENSP00000499133	P1
PURA	ENST00000505703.2	c.82T>C	p.Ser28Pro	missense_variant	2/2	3		ENSP00000498560
PURA	ENST00000502351.1			downstream_gene_variant		2		ENSP00000498760

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1066850 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 510244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 19, 2021

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Benign	0.90
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.30	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.88	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.20
Sift	Benign	0.090	T
Sift4G	Benign	0.24	T
Polyphen		0.68	P
Vest4		0.25
MutPred		0.21		Loss of phosphorylation at S28 (P = 0.0013);
MVP		0.67
MPC		2.0
ClinPred		0.15	T
GERP RS		1.9
Varity_R		0.13
gMVP		0.18

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: rs1554129019; hg19: chr5-139493848;