rs7782939

Positions:

• chr7-16421268-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001101426.4(CRPPA):​c.55A>C​(p.Ser19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,297,340 control chromosomes in the GnomAD database, including 60,694 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6867 hom., cov: 33)
  • Exomes 𝑓: 0.30 (53827 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.69

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]

LOC105375168 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036817193).
• BP6: Variant 7-16421268-T-G is Benign according to our data. Variant chr7-16421268-T-G is described in ClinVar as [Benign]. Clinvar id is 129288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-16421268-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4	c.55A>C	p.Ser19Arg	missense_variant	1/10	ENST00000407010.7
LOC105375168	XR_007060223.1	n.297+286T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7	c.55A>C	p.Ser19Arg	missense_variant	1/10	5	NM_001101426.4	P1
CRPPA	ENST00000399310.3	c.55A>C	p.Ser19Arg	missense_variant	1/9	1
CRPPA	ENST00000674759.1	c.-46-14931A>C		intron_variant
CRPPA	ENST00000675257.1	c.-46-14931A>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45300 AN: 151428 Hom.: 6873 Cov.: 33

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.278

GnomAD3 exomes AF: 0.257 AC: 3585 AN: 13926 Hom.: 495 AF XY: 0.245 AC XY: 1746 AN XY: 7114

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.180

Gnomad SAS exome AF: 0.181

Gnomad FIN exome AF: 0.302

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.304 AC: 348776 AN: 1145802 Hom.: 53827 Cov.: 34 AF XY: 0.304 AC XY: 166475 AN XY: 548400

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.240

Gnomad4 EAS exome AF: 0.269

Gnomad4 SAS exome AF: 0.335

Gnomad4 FIN exome AF: 0.292

Gnomad4 NFE exome AF: 0.307

Gnomad4 OTH exome AF: 0.305

GnomAD4 genome AF: 0.299 AC: 45311 AN: 151538 Hom.: 6867 Cov.: 33 AF XY: 0.300 AC XY: 22202 AN XY: 74058

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.288

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.280

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.300

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.277

Alfa AF: 0.291 Hom.: 806

Bravo AF: 0.296

TwinsUK AF: 0.317 AC: 1174

ALSPAC AF: 0.320 AC: 1232

ExAC AF: 0.119 AC: 1435

Asia WGS AF: 0.337 AC: 1170 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ser19Arg in exon 1 of ISPD: This variant is not expected to have clinical sign ificance because it has been identified in 39.9% (71/178) of English and Scottis h chromosomes from a broad population by the 1000 Genomes Project (http://www.nc bi.nlm.nih.gov/projects/SNP; dbSNP rs7782939). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Congenital Muscular Dystrophy, alpha-dystroglycan related Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.4
DANN	Benign	0.79
DEOGEN2	Benign	0.0014	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.14
Sift	Benign	0.88	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.0	B;.
Vest4		0.028
MutPred		0.24		Gain of methylation at S19 (P = 0.0183);Gain of methylation at S19 (P = 0.0183);
MPC		0.060
ClinPred		0.0010	T
GERP RS		-3.6
Varity_R		0.046
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs7782939; hg19: chr7-16460893; COSMIC: COSV67907237;