rs145564018

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_021971.4(GMPPB):​c.402+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GMPPB
NM_021971.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.64
Variant links:
Genes affected
GMPPB (HGNC:22932): (GDP-mannose pyrophosphorylase B) This gene is thought to encode a GDP-mannose pyrophosphorylase. The encoded protein catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, a reaction involved in the production of N-linked oligosaccharides. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jan 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-49722971-C-T is Pathogenic according to our data. Variant chr3-49722971-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 570106.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-49722971-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GMPPBNM_021971.4 linkuse as main transcriptc.402+1G>A splice_donor_variant, intron_variant ENST00000308388.7 NP_068806.2 Q9Y5P6-1
GMPPBNM_013334.4 linkuse as main transcriptc.402+1G>A splice_donor_variant, intron_variant NP_037466.3 Q9Y5P6-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GMPPBENST00000308388.7 linkuse as main transcriptc.402+1G>A splice_donor_variant, intron_variant 1 NM_021971.4 ENSP00000311130.6 Q9Y5P6-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152188
Hom.:
0
Cov.:
33
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461034
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
726856
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152188
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74344
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000103
Hom.:
0
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14;C3809221:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14;C4518000:Autosomal recessive limb-girdle muscular dystrophy type 2T Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 10, 2023For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 570106). Disruption of this splice site has been observed in individual(s) with clinical features of GMPPB-associated conditions (PMID: 26310427; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs145564018, gnomAD 0.007%). This sequence change affects a donor splice site in intron 4 of the GMPPB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GMPPB are known to be pathogenic (PMID: 23768512, 26310427). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.46
Position offset: -11
DS_DL_spliceai
1.0
Position offset: 1

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.

Other links and lift over

dbSNP: rs145564018; hg19: chr3-49760404; API