7-16258455-G-T

Position:

chr7-16258455-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001101426.4(CRPPA):c.1054C>A(p.Gln352Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,603,468 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.780

Variant links:

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 links:

CRPPA-AS1 (HGNC:48962): (CRPPA antisense RNA 1)

CRPPA-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002675265).

BP6

Variant 7-16258455-G-T is Benign according to our data. Variant chr7-16258455-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198766.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}. Variant chr7-16258455-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00243 (3524/1451372) while in subpopulation NFE AF= 0.00302 (3344/1106488). AF 95% confidence interval is 0.00294. There are 9 homozygotes in gnomad4_exome. There are 1722 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRPPA	NM_001101426.4 link	c.1054C>A	p.Gln352Lys	missense_variant	8/10	ENST00000407010.7	NP_001094896.1	A4D126-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7 link	c.1054C>A	p.Gln352Lys	missense_variant	8/10	5	NM_001101426.4	ENSP00000385478.2		A4D126-1

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

213

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000850

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00232

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00137

AC:

327

AN:

238306

Hom.:

AF XY:

0.00142

AC XY:

184

AN XY:

129224

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.000723

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000313

Gnomad FIN exome

AF:

0.000427

Gnomad NFE exome

AF:

0.00268

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.00243

AC:

3524

AN:

1451372

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

1722

AN XY:

721608

show subpopulations

Gnomad4 AFR exome

AF:

0.000242

Gnomad4 AMR exome

AF:

0.000115

Gnomad4 ASJ exome

AF:

0.000620

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000249

Gnomad4 FIN exome

AF:

0.000776

Gnomad4 NFE exome

AF:

0.00302

Gnomad4 OTH exome

AF:

0.00145

GnomAD4 genome

AF:

0.00140

AC:

213

AN:

152096

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000850

Gnomad4 NFE

AF:

0.00233

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000548

Hom.:

Bravo

AF:

0.00139

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000554

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00196

AC:

236

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CRPPA: BP4 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital Muscular Dystrophy, alpha-dystroglycan related

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.0064

T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.8

L;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.070

N;N

REVEL

Benign

0.060

Sift

Benign

0.59

T;T

Sift4G

Benign

0.90

T;T

Polyphen

0.085

B;.

Vest4

0.18

MVP

0.49

MPC

0.070

ClinPred

0.0012

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over