rs1554371369

Positions:

Variant summary

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

The NM_001101426.4(CRPPA):c.165del(p.Cys56AlafsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000407 in 1,178,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRPPA
NM_001101426.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: -0.925

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-16421157-AC-A is Pathogenic according to our data. Variant chr7-16421157-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-16421157-AC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRPPA	NM_001101426.4 linkuse as main transcript	c.165del	p.Cys56AlafsTer35	frameshift_variant	1/10	ENST00000407010.7	NP_001094896.1
LOC105375168	XR_007060223.1 linkuse as main transcript	n.297+181del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7 linkuse as main transcript	c.165del	p.Cys56AlafsTer35	frameshift_variant	1/10	5	NM_001101426.4	ENSP00000385478	P1	A4D126-1
CRPPA	ENST00000399310.3 linkuse as main transcript	c.165del	p.Cys56AlafsTer35	frameshift_variant	1/9	1		ENSP00000382249		A4D126-2
CRPPA	ENST00000674759.1 linkuse as main transcript	c.-46-14821del		intron_variant				ENSP00000502749
CRPPA	ENST00000675257.1 linkuse as main transcript	c.-46-14821del		intron_variant				ENSP00000501664

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151252

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000239

AC:

AN:

16718

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

8356

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00199

Gnomad ASJ exome

AF:

0.00284

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000333

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000407

AC:

AN:

1178964

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

568976

show subpopulations

Gnomad4 AFR exome

AF:

0.0000422

Gnomad4 AMR exome

AF:

0.000204

Gnomad4 ASJ exome

AF:

0.000124

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000384

Gnomad4 FIN exome

AF:

0.0000244

Gnomad4 NFE exome

AF:

0.0000269

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000661

AC:

AN:

151252

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73836

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2018

A variant that is likely pathogenic has been identified in the ISPD gene. The c.165delG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.165delG variant is not observed in large population cohorts (Lek et al., 2016). The c.165delG likely pathogenic variant causes a frameshift starting with codon Cysteine 56, changes this amino acid to a Alanine residue and creates a premature Stop codon at position 35 of the new reading frame, denoted p.Cys56AlafsX35. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817140). This variant has not been reported in the literature in individuals affected with ISPD-related conditions. 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 sequence change creates a premature translational stop signal (p.Cys56Alafs*35) 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