rs1036959263

Positions:

• chr7-16421163-C-A
• chr7-16421163-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001101426.4(CRPPA):​c.160G>T​(p.Gly54Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G54A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.17

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-16421162-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 156454.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4	c.160G>T	p.Gly54Trp	missense_variant	1/10	ENST00000407010.7
LOC105375168	XR_007060223.1	n.297+181C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7	c.160G>T	p.Gly54Trp	missense_variant	1/10	5	NM_001101426.4	P1
CRPPA	ENST00000399310.3	c.160G>T	p.Gly54Trp	missense_variant	1/9	1
CRPPA	ENST00000674759.1	c.-46-14826G>T		intron_variant
CRPPA	ENST00000675257.1	c.-46-14826G>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1185472 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 572814

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 28, 2018

This sequence change replaces glycine with tryptophan at codon 54 of the ISPD protein (p.Gly54Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with ISPD-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. A different missense substitution at this codon (p.Gly54Ala) has been reported as homozygous in individuals affected with muscular dystrophy-dystroglycanopathy (PMID: 23390185). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.86
MutPred		0.71		Loss of disorder (P = 0.0078);Loss of disorder (P = 0.0078);
MVP		0.85
MPC		0.38
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.89
gMVP		0.90

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: rs1036959263; hg19: chr7-16460788;