7-16406048-A-T

Variant names:

• chr7-16406048-A-T
• rs6461252
• NM_001101426.4:c.534+13T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001101426.4(CRPPA):​c.534+13T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 1,606,504 control chromosomes in the GnomAD database, including 150,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18238 hom., cov: 32)
  • Exomes 𝑓: 0.42 (132550 hom.)
• Consequence: CRPPA NM_001101426.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.203
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-16406048-A-T is Benign according to our data. Variant chr7-16406048-A-T is described in ClinVar as Benign. ClinVar VariationId is 226675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101426.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	NM_001101426.4	MANE Select	c.534+13T>A		intron	N/A	NP_001094896.1
	CRPPA	NM_001368197.1		c.534+13T>A		intron	N/A	NP_001355126.1
	CRPPA	NM_001101417.4		c.534+13T>A		intron	N/A	NP_001094887.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.534+13T>A		intron	N/A	ENSP00000385478.2
	CRPPA	ENST00000399310.3	TSL:1	c.534+13T>A		intron	N/A	ENSP00000382249.3
	CRPPA	ENST00000856526.1		c.534+13T>A		intron	N/A	ENSP00000526585.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72377 AN: 151912 Hom.: 18213 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.442

GnomAD2 exomes AF: 0.452 AC: 109438 AN: 242260 AF XY: 0.452

Gnomad AFR exome AF: 0.632

Gnomad AMR exome AF: 0.461

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.549

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.422 AC: 614068 AN: 1454474 Hom.: 132550 Cov.: 34 AF XY: 0.425 AC XY: 306969 AN XY: 722614

African (AFR) AF: 0.636 AC: 21246 AN: 33386

American (AMR) AF: 0.470 AC: 20704 AN: 44062

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 10242 AN: 26022

East Asian (EAS) AF: 0.549 AC: 21719 AN: 39582

South Asian (SAS) AF: 0.573 AC: 49007 AN: 85592

European-Finnish (FIN) AF: 0.412 AC: 21880 AN: 53146

Middle Eastern (MID) AF: 0.392 AC: 2255 AN: 5752

European-Non Finnish (NFE) AF: 0.398 AC: 440630 AN: 1106798

Other (OTH) AF: 0.439 AC: 26385 AN: 60134

GnomAD4 genome AF: 0.477 AC: 72458 AN: 152030 Hom.: 18238 Cov.: 32 AF XY: 0.481 AC XY: 35715 AN XY: 74328

African (AFR) AF: 0.634 AC: 26306 AN: 41470

American (AMR) AF: 0.459 AC: 7007 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1344 AN: 3472

East Asian (EAS) AF: 0.548 AC: 2829 AN: 5162

South Asian (SAS) AF: 0.562 AC: 2708 AN: 4820

European-Finnish (FIN) AF: 0.406 AC: 4288 AN: 10568

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.391 AC: 26567 AN: 67958

Other (OTH) AF: 0.444 AC: 938 AN: 2112

Alfa AF: 0.418 Hom.: 2614

Bravo AF: 0.485

Asia WGS AF: 0.550 AC: 1915 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Congenital Muscular Dystrophy, alpha-dystroglycan related (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.3
DANN	Benign	0.71
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs6461252; hg19: chr7-16445673; COSMIC: COSV67904196;