chr7-16278181-T-C

Position:

chr7-16278181-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001101426.4(CRPPA):c.881A>G(p.Asp294Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,583,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.837

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 (HGNC:):

CRPPA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08025131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRPPA	NM_001101426.4 linkuse as main transcript	c.881A>G	p.Asp294Gly	missense_variant	6/10	ENST00000407010.7	NP_001094896.1	A4D126-1
CRPPA	NM_001368197.1 linkuse as main transcript	c.776A>G	p.Asp259Gly	missense_variant	5/9		NP_001355126.1
CRPPA	NM_001101417.4 linkuse as main transcript	c.731A>G	p.Asp244Gly	missense_variant	5/9		NP_001094887.1	A4D126-2A0A140VJM1
CRPPA	NR_160656.1 linkuse as main transcript	n.946A>G		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7 linkuse as main transcript	c.881A>G	p.Asp294Gly	missense_variant	6/10	5	NM_001101426.4	ENSP00000385478.2		A4D126-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000733

AC:

AN:

232016

Hom.:

AF XY:

0.0000794

AC XY:

AN XY:

125876

show subpopulations

Gnomad AFR exome

AF:

0.0000714

Gnomad AMR exome

AF:

0.0000310

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.000145

AC:

208

AN:

1431390

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

103

AN XY:

712452

show subpopulations

Gnomad4 AFR exome

AF:

0.0000610

Gnomad4 AMR exome

AF:

0.0000465

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000180

Gnomad4 OTH exome

AF:

0.000135

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000581

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2016	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 294 of the ISPD protein (p.Asp294Gly). This variant is present in population databases (rs547473863, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ISPD-related conditions. ClinVar contains an entry for this variant (Variation ID: 290098). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ISPD protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.3

L;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.25

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.024

D;D

Polyphen

0.93

P;.

Vest4

0.32

MVP

0.74

MPC

0.070

ClinPred

0.023

GERP RS

2.5

Varity_R

0.31

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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