rs587777798

chr7-16258392-AAAC-Achr7-16258392-AAAC-AAACAAC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_001101426.4(CRPPA):c.1114_1116del(p.Val372del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000266 in 1,580,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: CRPPA NM_001101426.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.65

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-AS1 (HGNC:48962): (CRPPA antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001101426.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 7-16258392-AAAC-A is Pathogenic according to our data. Variant chr7-16258392-AAAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 156455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-16258392-AAAC-A is described in Lovd as [Pathogenic]. Variant chr7-16258392-AAAC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4	c.1114_1116del	p.Val372del	inframe_deletion	8/10	ENST00000407010.7
CRPPA-AS1	NR_038947.1	n.241-7824_241-7822del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7	c.1114_1116del	p.Val372del	inframe_deletion	8/10	5	NM_001101426.4	P1
CRPPA-AS1	ENST00000438573.5	n.222-3496_222-3494del		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000252 AC: 36 AN: 1428066 Hom.: 0 AF XY: 0.0000239 AC XY: 17 AN XY: 711136

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.0000714

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.0000848

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.0000193

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74302

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Also known as ISPD c.1114_1116del p.(Val372del); This variant is associated with the following publications: (PMID: 23288328, 34485198, 27234031, 23390185, 31127727, 30708323, 31375477, 37526466, 34307571) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -

Autosomal recessive limb-girdle muscular dystrophy type 2U Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 05, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

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

Dec 22, 2022

ClinVar contains an entry for this variant (Variation ID: 156455). This variant has been observed in individual(s) with ISPD-related conditions (PMID: 23288328, 23390185, 27234031, 31127727). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.1114_1116del, results in the deletion of 1 amino acid(s) of the ISPD protein (p.Val372del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

Computational scores

Source: dbNSFP v4.3

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: rs587777798; hg19: chr7-16298017;