rs186882839

chr7-16091697-A-Gchr7-16091697-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001101426.4(CRPPA):c.1354T>C(p.Ter452ArgextTer28) variant causes a stop lost change. The variant allele was found at a frequency of 0.000000727 in 1,375,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CRPPA NM_001101426.4 stop_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.76

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-16091697-A-G is Pathogenic according to our data. Variant chr7-16091697-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 872213.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4	c.1354T>C	p.Ter452ArgextTer28	stop_lost	10/10	ENST00000407010.7
CRPPA	NM_001368197.1	c.1249T>C	p.Ter417ArgextTer28	stop_lost	9/9
CRPPA	NM_001101417.4	c.1204T>C	p.Ter402ArgextTer28	stop_lost	9/9
CRPPA	NR_160656.1	n.1419T>C		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7	c.1354T>C	p.Ter452ArgextTer28	stop_lost	10/10	5	NM_001101426.4	P1
CRPPA	ENST00000399310.3	c.1204T>C	p.Ter402ArgextTer28	stop_lost	9/9	1
CRPPA	ENST00000676325.1	c.1051T>C	p.Ter351ArgextTer28	stop_lost	11/11
CRPPA	ENST00000675257.1	c.946T>C	p.Ter316ArgextTer28	stop_lost	10/10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375500 Hom.: 0 Cov.: 24 AF XY: 0.00000147 AC XY: 1 AN XY: 680340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.44e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2019

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 872213). This protein extension has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 22522420, 28973083). This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the ISPD mRNA. It is expected to extend the length of the ISPD protein by 28 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	18
Dann	Benign	0.87
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	N;N
Vest4		0.081
GERP RS		5.5

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: rs186882839; hg19: chr7-16131322;