7-16088408-C-T

Variant names:

• chr7-16088408-C-T
• rs886062143
• NM_001101426.4:c.*3287G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001101426.4(CRPPA):​c.*3287G>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 0.0000086 (0 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: CRPPA NM_001101426.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.236
• Publications: 0 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 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myopathy caused by variation in CRPPA

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2U

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4	c.*3287G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000407010.7	NP_001094896.1
CRPPA	NR_160656.1	n.4708G>A		non_coding_transcript_exon_variant	Exon 8 of 8
CRPPA	NM_001368197.1	c.*3287G>A		3_prime_UTR_variant	Exon 9 of 9		NP_001355126.1
CRPPA	NM_001101417.4	c.*3287G>A		3_prime_UTR_variant	Exon 9 of 9		NP_001094887.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7	c.*3287G>A		3_prime_UTR_variant	Exon 10 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes AF: 0.00000865 AC: 1 AN: 115648 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000865 AC: 1 AN: 115648 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 54164

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

African (AFR) AF: 0.0000272 AC: 1 AN: 36706

American (AMR) AF: 0.00 AC: 0 AN: 8814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2952

East Asian (EAS) AF: 0.00 AC: 0 AN: 3882

South Asian (SAS) AF: 0.00 AC: 0 AN: 2816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53248

Other (OTH) AF: 0.00 AC: 0 AN: 1398

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital Muscular Dystrophy, alpha-dystroglycan related Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.50
CADD	Benign	3.8
DANN	Benign	0.78
PhyloP100		0.24

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: rs886062143; hg19: chr7-16128033;