7-16421067-T-C

Variant names:

• chr7-16421067-T-C
• rs397514548
• NM_001101426.4:c.256A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001101426.4(CRPPA):​c.256A>G​(p.Arg86Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000897 in 1,114,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: CRPPA NM_001101426.4 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34
• Publications: 2 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

ENSG00000272537 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	NM_001101426.4	MANE Select	c.256A>G	p.Arg86Gly	missense splice_region	Exon 1 of 10	NP_001094896.1	A4D126-1
	CRPPA	NM_001368197.1		c.256A>G	p.Arg86Gly	missense splice_region	Exon 1 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.256A>G	p.Arg86Gly	missense splice_region	Exon 1 of 9	NP_001094887.1	A0A140VJM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.256A>G	p.Arg86Gly	missense splice_region	Exon 1 of 10	ENSP00000385478.2	A4D126-1
	CRPPA	ENST00000399310.3	TSL:1	c.256A>G	p.Arg86Gly	missense splice_region	Exon 1 of 9	ENSP00000382249.3	A4D126-2
	CRPPA	ENST00000856526.1		c.256A>G	p.Arg86Gly	missense splice_region	Exon 1 of 8	ENSP00000526585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 13780 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.97e-7 AC: 1 AN: 1114916 Hom.: 0 Cov.: 31 AF XY: 0.00000189 AC XY: 1 AN XY: 529974

African (AFR) AF: 0.00 AC: 0 AN: 23130

American (AMR) AF: 0.00 AC: 0 AN: 8496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14672

East Asian (EAS) AF: 0.00 AC: 0 AN: 26658

South Asian (SAS) AF: 0.00 AC: 0 AN: 25440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4580

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 930742

Other (OTH) AF: 0.00 AC: 0 AN: 44572

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2U (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.053
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.49
Sift	Benign	0.034	D
Sift4G	Uncertain	0.013	D
Polyphen		0.16	B
Vest4		0.40
MutPred		0.45		Loss of solvent accessibility (P = 0.0159)
MVP		0.86
MPC		0.14
ClinPred		0.99	D
GERP RS		4.4
PromoterAI		-0.44	Neutral
Varity_R		0.68
gMVP		0.63
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397514548; hg19: chr7-16460692;