7-16088412-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001101426.4(CRPPA):c.*3283G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0084 (8 hom., cov: 16)
  • Failed GnomAD Quality Control
• Consequence: CRPPA NM_001101426.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.05

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00845 (956/113142) while in subpopulation AMR AF= 0.0115 (109/9504). AF 95% confidence interval is 0.0107. There are 8 homozygotes in gnomad4. There are 415 alleles in male gnomad4 subpopulation. Median coverage is 16. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4	c.*3283G>A		3_prime_UTR_variant	10/10	ENST00000407010.7
CRPPA	NM_001101417.4	c.*3283G>A		3_prime_UTR_variant	9/9
CRPPA	NM_001368197.1	c.*3283G>A		3_prime_UTR_variant	9/9
CRPPA	NR_160656.1	n.4704G>A		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7	c.*3283G>A		3_prime_UTR_variant	10/10	5	NM_001101426.4	P1

Frequencies

GnomAD3 genomes AF: 0.00844 AC: 955 AN: 113150 Hom.: 8 Cov.: 16

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.0631

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00102

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00365

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.0220

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0123

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.00845 AC: 956 AN: 113142 Hom.: 8 Cov.: 16 AF XY: 0.00790 AC XY: 415 AN XY: 52530

Gnomad4 AFR AF: 0.00264

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00102

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00367

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.0122

Alfa AF: 0.00145 Hom.: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital Muscular Dystrophy, alpha-dystroglycan related Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.41
Dann	Benign	0.86

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: rs370712733; hg19: chr7-16128037;