rs369832637

Variant names:

• chr7-16258936-T-C
• rs369832637
• NM_001101426.4:c.1010A>G

Variant summary

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

The NM_001101426.4(CRPPA):​c.1010A>G​(p.Asn337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,609,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N337H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.823
• 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-AS1 (HGNC:48962): (CRPPA antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0331133).

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.1010A>G	p.Asn337Ser	missense	Exon 7 of 10	NP_001094896.1
	CRPPA	NM_001368197.1		c.905A>G	p.Asn302Ser	missense	Exon 6 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.860A>G	p.Asn287Ser	missense	Exon 6 of 9	NP_001094887.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.1010A>G	p.Asn337Ser	missense	Exon 7 of 10	ENSP00000385478.2
	CRPPA	ENST00000399310.3	TSL:1	c.860A>G	p.Asn287Ser	missense	Exon 6 of 9	ENSP00000382249.3
	CRPPA-AS1	ENST00000438573.5	TSL:1	n.222-2963T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151994 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

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

GnomAD2 exomes AF: 0.000114 AC: 28 AN: 245382 AF XY: 0.0000977

Gnomad AFR exome AF: 0.000263

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1457248 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 724794

African (AFR) AF: 0.000420 AC: 14 AN: 33322

American (AMR) AF: 0.00 AC: 0 AN: 44182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.000354 AC: 14 AN: 39534

South Asian (SAS) AF: 0.00 AC: 0 AN: 85584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109532

Other (OTH) AF: 0.0000499 AC: 3 AN: 60160

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151994 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74240

African (AFR) AF: 0.000338 AC: 14 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67926

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.000792 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.3
DANN	Benign	0.97
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.32	N
PhyloP100		-0.82
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Benign	0.23	T
Sift4G	Benign	0.19	T
Polyphen		0.12	B
Vest4		0.18
MVP		0.60
MPC		0.050
ClinPred		0.014	T
GERP RS		-2.2
Varity_R		0.15
gMVP		0.57
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369832637; hg19: chr7-16298561;