rs587777798

Variant names:

• chr7-16258392-AAAC-A
• rs587777798
• NM_001101426.4:c.1114_1116delGTT

Your query was ambiguous. Multiple possible variants found:

• chr7-16258392-AAAC-A
• chr7-16258392-AAAC-AAACAAC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_001101426.4(CRPPA):​c.1114_1116delGTT​(p.Val372del) variant causes a conservative 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 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.65
• Publications: 6 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 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 156455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101426.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	NM_001101426.4	MANE Select	c.1114_1116delGTT	p.Val372del	conservative_inframe_deletion	Exon 8 of 10	NP_001094896.1	A4D126-1
	CRPPA	NM_001368197.1		c.1009_1011delGTT	p.Val337del	conservative_inframe_deletion	Exon 7 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.964_966delGTT	p.Val322del	conservative_inframe_deletion	Exon 7 of 9	NP_001094887.1	A0A140VJM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.1114_1116delGTT	p.Val372del	conservative_inframe_deletion	Exon 8 of 10	ENSP00000385478.2	A4D126-1
	CRPPA	ENST00000399310.3	TSL:1	c.964_966delGTT	p.Val322del	conservative_inframe_deletion	Exon 7 of 9	ENSP00000382249.3	A4D126-2
	CRPPA-AS1	ENST00000438573.5	TSL:1	n.222-3496_222-3494delACA		intron	N/A

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

GnomAD2 exomes AF: 0.0000738 AC: 17 AN: 230262 AF XY: 0.0000720

Gnomad AFR exome AF: 0.000140

Gnomad AMR exome AF: 0.0000969

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000119

Gnomad FIN exome AF: 0.0000481

Gnomad NFE exome AF: 0.0000378

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000309 AC: 1 AN: 32360

American (AMR) AF: 0.0000714 AC: 3 AN: 42018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39170

South Asian (SAS) AF: 0.0000848 AC: 7 AN: 82526

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.0000193 AC: 21 AN: 1089024

Other (OTH) AF: 0.00 AC: 0 AN: 59122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000857425), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0000483 AC: 2 AN: 41438

American (AMR) AF: 0.0000657 AC: 1 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2U (2)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6
Mutation Taster		=36/64	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777798; hg19: chr7-16298017;