chr7-16087672-G-T

Variant names:

• chr7-16087672-G-T
• rs12539174
• NM_001101426.4:c.*4023C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001101426.4(CRPPA):​c.*4023C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 151,700 control chromosomes in the GnomAD database, including 9,650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (9650 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CRPPA NM_001101426.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.155
• Publications: 7 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-16087672-G-T is Benign according to our data. Variant chr7-16087672-G-T is described in ClinVar as [Benign]. Clinvar id is 359485.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4	c.*4023C>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000407010.7	NP_001094896.1
CRPPA	NR_160656.1	n.5444C>A		non_coding_transcript_exon_variant	Exon 8 of 8
CRPPA	NM_001368197.1	c.*4023C>A		3_prime_UTR_variant	Exon 9 of 9		NP_001355126.1
CRPPA	NM_001101417.4	c.*4023C>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.*4023C>A		3_prime_UTR_variant	Exon 10 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50021 AN: 151584 Hom.: 9641 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.561

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.326

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.330 AC: 50027 AN: 151700 Hom.: 9650 Cov.: 32 AF XY: 0.333 AC XY: 24686 AN XY: 74110

African (AFR) AF: 0.127 AC: 5259 AN: 41398

American (AMR) AF: 0.341 AC: 5200 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3470

East Asian (EAS) AF: 0.325 AC: 1675 AN: 5148

South Asian (SAS) AF: 0.559 AC: 2693 AN: 4820

European-Finnish (FIN) AF: 0.453 AC: 4743 AN: 10468

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28505 AN: 67846

Other (OTH) AF: 0.329 AC: 693 AN: 2106

Alfa AF: 0.383 Hom.: 38579

Bravo AF: 0.307

Asia WGS AF: 0.432 AC: 1491 AN: 3448

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital Muscular Dystrophy, alpha-dystroglycan related Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.93
DANN	Benign	0.63
PhyloP100		0.15

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: rs12539174; hg19: chr7-16127297;