rs1292380177

Positions:

• chr7-16421102-C-A
• chr7-16421102-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001101426.4(CRPPA):​c.221G>T​(p.Arg74Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000871 in 1,148,760 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R74T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.27

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4	c.221G>T	p.Arg74Met	missense_variant	1/10	ENST00000407010.7
LOC105375168	XR_007060223.1	n.297+120C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7	c.221G>T	p.Arg74Met	missense_variant	1/10	5	NM_001101426.4	P1
CRPPA	ENST00000399310.3	c.221G>T	p.Arg74Met	missense_variant	1/9	1
CRPPA	ENST00000674759.1	c.-46-14765G>T		intron_variant
CRPPA	ENST00000675257.1	c.-46-14765G>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.71e-7 AC: 1 AN: 1148760 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 550870

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: 0.0000256

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

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	30
DANN	Benign	0.97
DEOGEN2	Uncertain	0.65	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.046	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		0.99	D;.
Vest4		0.60
MutPred		0.64		Loss of catalytic residue at R74 (P = 0.0148);Loss of catalytic residue at R74 (P = 0.0148);
MVP		0.63
MPC		0.25
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.79
gMVP		0.79

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: rs1292380177; hg19: chr7-16460727;