rs397514548

chr7-16421067-T-Achr7-16421067-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP3_Moderate PP5

The NM_001101426.4(CRPPA):c.256A>T(p.Arg86Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRPPA NM_001101426.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.34

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]

LOC105375168 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-16421067-T-A is Pathogenic according to our data. Variant chr7-16421067-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 39613.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-16421067-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4	c.256A>T	p.Arg86Ter	stop_gained, splice_region_variant	1/10	ENST00000407010.7
LOC105375168	XR_007060223.1	n.297+85T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7	c.256A>T	p.Arg86Ter	stop_gained, splice_region_variant	1/10	5	NM_001101426.4	P1
CRPPA	ENST00000399310.3	c.256A>T	p.Arg86Ter	stop_gained, splice_region_variant	1/9	1
CRPPA	ENST00000674759.1	c.-46-14730A>T		intron_variant
CRPPA	ENST00000675257.1	c.-46-14730A>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 07, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	50
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
Vest4		0.68
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514548; hg19: chr7-16460692;