rs61734789

Variant names:

• chr7-16406188-G-A
• rs61734789
• NM_001101426.4:c.407C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001101426.4(CRPPA):​c.407C>T​(p.Ala136Val) variant causes a missense change. The variant allele was found at a frequency of 0.0365 in 1,613,930 control chromosomes in the GnomAD database, including 1,333 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (59 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1274 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.21

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010987341).
• BP6: Variant 7-16406188-G-A is Benign according to our data. Variant chr7-16406188-G-A is described in ClinVar as [Benign]. Clinvar id is 129287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-16406188-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.024 (3654/152308) while in subpopulation NFE AF= 0.0381 (2594/68026). AF 95% confidence interval is 0.0369. There are 59 homozygotes in gnomad4. There are 1700 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 10	ENST00000407010.7	NP_001094896.1
CRPPA	NM_001368197.1	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 9		NP_001355126.1
CRPPA	NM_001101417.4	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 9		NP_001094887.1
CRPPA	NR_160656.1	n.623C>T		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7	c.407C>T	p.Ala136Val	missense_variant	Exon 2 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3657 AN: 152190 Hom.: 59 Cov.: 33

Gnomad AFR AF: 0.00849

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0382

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0232 AC: 5776 AN: 249146 Hom.: 92 AF XY: 0.0239 AC XY: 3229 AN XY: 135164

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.00864

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0378 AC: 55266 AN: 1461622 Hom.: 1274 Cov.: 33 AF XY: 0.0367 AC XY: 26681 AN XY: 727106

Gnomad4 AFR exome AF: 0.00612

Gnomad4 AMR exome AF: 0.00899

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.0246

Gnomad4 NFE exome AF: 0.0451

Gnomad4 OTH exome AF: 0.0330

GnomAD4 genome AF: 0.0240 AC: 3654 AN: 152308 Hom.: 59 Cov.: 33 AF XY: 0.0228 AC XY: 1700 AN XY: 74468

Gnomad4 AFR AF: 0.00847

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0236

Gnomad4 NFE AF: 0.0381

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0342 Hom.: 180

Bravo AF: 0.0231

ESP6500AA AF: 0.00937 AC: 36

ESP6500EA AF: 0.0352 AC: 290

ExAC AF: 0.0241 AC: 2909

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0329

EpiControl AF: 0.0350

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala136Val in exon 2 of ISPD: This variant is not expected to have clinical sig nificance because it has been identified in 3.5% (290/8230) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs61734789). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Oct 20, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.11	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.53	P;.
Vest4		0.081
MPC		0.072
ClinPred		0.013	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.66

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: rs61734789; hg19: chr7-16445813; COSMIC: COSV99063049;