rs773618224

chr1-151018650-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PP5_Very_Strong

The NM_021222.3(PRUNE1):c.316G>A(p.Asp106Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PRUNE1 NM_021222.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.63

Genes affected

PRUNE1 (HGNC:13420): (prune exopolyphosphatase 1) This gene encodes a member of the DHH protein superfamily of phosphoesterases. This protein has been found to function as both a nucleotide phosphodiesterase and an exopolyphosphatase. This protein is believed to stimulate cancer progression and metastases through the induction of cell motility. A pseuodgene has been identified on chromosome 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS1: Transcript NM_021222.3 (PRUNE1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a short_sequence_motif DHH motif (size 2) in uniprot entity PRUN1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_021222.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-151018650-G-A is Pathogenic according to our data. Variant chr1-151018650-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-151018650-G-A is described in Lovd as [Pathogenic]. Variant chr1-151018650-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRUNE1	NM_021222.3	c.316G>A	p.Asp106Asn	missense_variant	3/8	ENST00000271620.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRUNE1	ENST00000271620.8	c.316G>A	p.Asp106Asn	missense_variant	3/8	1	NM_021222.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251126 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461744 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152094 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74290

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000487 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.316G>A (p.Asp106Asn) in PRUNE1 gene has been reported to be homozygous in several individuals with syndromic intellectual disability (Karaca E et.al.,2015). Experimental studies show that missense change affect PRUNE1 function (Zollo M et.al .,2017). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Asp106Asn variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.00005177% is reported in gnomAD. The amino acid Asp at position 106 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	May 09, 2018	Observed as a homozygote. -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jan 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 29, 2019	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2021	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with PRUNE1-related neurodevelopmental conditions (PMID: 26539891, 28334956, 29797509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 402131). This variant is present in population databases (rs773618224, ExAC 0.02%). This sequence change replaces aspartic acid with asparagine at codon 106 of the PRUNE1 protein (p.Asp106Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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There are 3 more families with similar phenotype -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.63	T
Polyphen		1.0	.;D
Vest4		0.97
MutPred		0.82		.;Gain of catalytic residue at H107 (P = 0.1601);
MVP		0.56
MPC		0.70
ClinPred		0.58	D
GERP RS		5.0
Varity_R		0.43
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs773618224; hg19: chr1-150991126;