rs397515396

Variant names:

• chr7-16216198-C-A
• rs397515396
• NM_001101426.4:c.1120-1G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-16216198-C-A
• chr7-16216198-C-G
• chr7-16216198-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001101426.4(CRPPA):​c.1120-1G>T variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRPPA NM_001101426.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.90
• Publications: 3 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.097345136 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of 25, new splice context is: ttttcttgattttaaattAGtac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-16216198-C-A is Pathogenic according to our data. Variant chr7-16216198-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4	c.1120-1G>T		splice_acceptor_variant, intron_variant	Intron 8 of 9	ENST00000407010.7	NP_001094896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7	c.1120-1G>T		splice_acceptor_variant, intron_variant	Intron 8 of 9	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401712 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 698026

African (AFR) AF: 0.00 AC: 0 AN: 31274

American (AMR) AF: 0.00 AC: 0 AN: 38206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24662

East Asian (EAS) AF: 0.00 AC: 0 AN: 38990

South Asian (SAS) AF: 0.00 AC: 0 AN: 80018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072130

Other (OTH) AF: 0.00 AC: 0 AN: 58200

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000255 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 Pathogenic:2

Apr 21, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3, PM3_Supporting, -

May 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Mar 23, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U Pathogenic:1

Oct 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 8 of the ISPD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ISPD are known to be pathogenic (PMID: 23288328). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that disruption of this splice site affects ISPD function (PMID: 22522420). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 31561). Disruption of this splice site has been observed in individuals with Walker-Warburg syndrome (PMID: 22522420). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		3.9
GERP RS		5.2
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.97		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397515396; hg19: chr7-16255823; COSMIC: COSV101235317;