chr7-16421244-T-G

Position:

chr7-16421244-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001101426.4(CRPPA):c.79A>C(p.Thr27Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,327,884 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T27K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

CRPPA
NM_001101426.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.989

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:

LOC105375168 (HGNC:):

LOC105375168 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0045420527).

BP6

Variant 7-16421244-T-G is Benign according to our data. Variant chr7-16421244-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193158.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00205 (311/151868) while in subpopulation AFR AF= 0.00683 (283/41432). AF 95% confidence interval is 0.00618. There are 0 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4 linkuse as main transcript	c.79A>C	p.Thr27Pro	missense_variant	1/10	ENST00000407010.7
LOC105375168	XR_007060223.1 linkuse as main transcript	n.297+262T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7 linkuse as main transcript	c.79A>C	p.Thr27Pro	missense_variant	1/10	5	NM_001101426.4	P1	A4D126-1
CRPPA	ENST00000399310.3 linkuse as main transcript	c.79A>C	p.Thr27Pro	missense_variant	1/9	1			A4D126-2
CRPPA	ENST00000674759.1 linkuse as main transcript	c.-46-14907A>C		intron_variant
CRPPA	ENST00000675257.1 linkuse as main transcript	c.-46-14907A>C		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00205

AC:

311

AN:

151756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00685

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

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:

0.0000442

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.0000529

AC:

AN:

18908

Hom.:

AF XY:

0.000101

AC XY:

AN XY:

9888

show subpopulations

Gnomad AFR exome

AF:

0.00435

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000137

AC:

161

AN:

1176016

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

566132

show subpopulations

Gnomad4 AFR exome

AF:

0.00512

Gnomad4 AMR exome

AF:

0.000179

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:

0.00000934

Gnomad4 OTH exome

AF:

0.000593

GnomAD4 genome

AF:

0.00205

AC:

311

AN:

151868

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.00683

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000208

Hom.:

Bravo

AF:

0.00211

ExAC

AF:

0.000112

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 10, 2020	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2020	This variant is associated with the following publications: (PMID: 29382405) -

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

Invitae

Oct 18, 2022

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 27 of the ISPD protein (p.Thr27Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with muscular dystophy (PMID: 29382405). ClinVar contains an entry for this variant (Variation ID: 193158). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

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. -

CRPPA-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

6.9

DANN

Benign

0.61

DEOGEN2

Benign

0.00053

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.24

T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.73

N;N

REVEL

Benign

0.16

Sift

Benign

0.037

D;D

Sift4G

Benign

0.34

T;T

Polyphen

0.0060

B;.

Vest4

0.12

MutPred

0.12

Loss of phosphorylation at T27 (P = 0.0221);Loss of phosphorylation at T27 (P = 0.0221);

MVP

0.20

MPC

0.076

ClinPred

0.036

GERP RS

3.1

Varity_R

0.10

gMVP

0.29

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