rs886041302

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001101426.4(CRPPA):c.53_54insT(p.Ser19GlufsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,296,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L18L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CRPPA
NM_001101426.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 0.581

Variant links:

Genes affected

CRPPA (HGNC:37276): (CDP-L-ribitol pyrophosphorylase A) This gene encodes a 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase-like protein. Mutations in this gene are the cause of Walker-Warburg syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

CRPPA links:

LOC105375168 (HGNC:):

LOC105375168 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 71 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-16421269-C-CA is Pathogenic according to our data. Variant chr7-16421269-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4 linkuse as main transcript	c.53_54insT	p.Ser19GlufsTer97	frameshift_variant	1/10	ENST00000407010.7
LOC105375168	XR_007060223.1 linkuse as main transcript	n.297+288dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7 linkuse as main transcript	c.53_54insT	p.Ser19GlufsTer97	frameshift_variant	1/10	5	NM_001101426.4	P1	A4D126-1
CRPPA	ENST00000399310.3 linkuse as main transcript	c.53_54insT	p.Ser19GlufsTer97	frameshift_variant	1/9	1			A4D126-2
CRPPA	ENST00000674759.1 linkuse as main transcript	c.-46-14933_-46-14932insT		intron_variant
CRPPA	ENST00000675257.1 linkuse as main transcript	c.-46-14933_-46-14932insT		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

151810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000114

AC:

130

AN:

1144948

Hom.:

Cov.:

AF XY:

0.0000912

AC XY:

AN XY:

547966

show subpopulations

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:

0.000129

Gnomad4 OTH exome

AF:

0.000175

GnomAD4 genome

AF:

0.000119

AC:

AN:

151810

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74160

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000907

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2018	The c.53dupT pathogenic variant in the ISPD gene has been previously reported in individuals with ISPD-related disorders who harbor an additional ISPD variant (Roscioli et al., 2012; Cirak et al., 2013). The c.53dupT variant causes a frameshift starting with codon Serine 19, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 97 of the new reading frame, denoted p.Ser19GlufsX97. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.53dupT variant is not observed at a significant frequency in individuals undergoing testing at GeneDx. Therefore, we interpret c.53dupT as a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2021	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 26, 2022	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2021

The c.53dupT (p.S19Efs*97) alteration, located in exon 1 (coding exon 1) of the ISPD gene, consists of a duplication of T at position 53, causing a translational frameshift with a predicted alternate stop codon after 97 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, this alteration is classified as pathogenic. -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 21, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279985). This premature translational stop signal has been observed in individuals with Walker-Warburg syndrome or autosomal recessive limb girdle muscular dystrophy with intellectual disability (PMID: 2328832, 22522421). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Ser19Glufs*97) in the ISPD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ISPD are known to be pathogenic (PMID: 23288328). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over