rs147785187
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005142.3(CBLIF):c.79+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,608,564 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 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )
Consequence
CBLIF
NM_005142.3 splice_donor, intron
NM_005142.3 splice_donor, intron
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.41
Genes affected
CBLIF (HGNC:4268): (cobalamin binding intrinsic factor) This gene is a member of the cobalamin transport protein family. It encodes a glycoprotein secreted by parietal cells of the gastric mucosa and is required for adequate absorption of vitamin B12. Vitamin B12 is necessary for erythrocyte maturation and mutations in this gene may lead to congenital pernicious anemia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-59845374-C-T is Pathogenic according to our data. Variant chr11-59845374-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 439755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-59845374-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CBLIF | NM_005142.3 | c.79+1G>A | splice_donor_variant, intron_variant | ENST00000257248.3 | NP_005133.2 | |||
| CBLIF | XM_011544939.4 | c.79+1G>A | splice_donor_variant, intron_variant | XP_011543241.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CBLIF | ENST00000257248.3 | c.79+1G>A | splice_donor_variant, intron_variant | 1 | NM_005142.3 | ENSP00000257248.2 | ||||
| CBLIF | ENST00000525058.5 | n.80G>A | non_coding_transcript_exon_variant | 1/9 | 2 | ENSP00000433196.1 | ||||
| CBLIF | ENST00000532070.1 | n.125+1G>A | splice_donor_variant, intron_variant | 2 |
Frequencies
GnomAD3 genomes 0.000164 AC: 25AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000195 AC: 49AN: 251232Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135784
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GnomAD4 exome AF: 0.000266 AC: 387AN: 1456402Hom.: 0 Cov.: 29 AF XY: 0.000232 AC XY: 168AN XY: 724910
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GnomAD4 genome 0.000164 AC: 25AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74342
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary intrinsic factor deficiency Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 05, 2018 | The c.79+1G>A variant in GIF (also referred to as CBLIF) has been reported in at least 7 compound heterozygous and 4 homozygous individuals with intrinsic facto r deficiency and segregated with disease in 2 affected relatives from 2 families (Ferrand 2015, Overgaard 2010, Stray-Pedersen 2017, Tanner 2005, Tanner 2012). It has also been identified in 0.03% (41/28970) of European chromosomes by gnomA D (http://gnomad.broadinstitute.org). This variant has also been reported in Cli nVar (Variation ID 439755). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the GIF gene is an established disease mecha nism in autosomal recessive intrinsic factor deficiency. In summary, this varian t meets criteria to be classified as pathogenic for autosomal recessive intrinsi c factor deficiency. ACMG/AMP Criteria applied: PM3_Strong, PVS1_Strong. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 07, 2024 | This sequence change affects a donor splice site in intron 1 of the GIF 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 GIF are known to be pathogenic (PMID: 14576042, 22929189). This variant is present in population databases (rs147785187, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with intrinsic factor deficiency (PMID: 15738392, 20408840, 22929189, 25308559). ClinVar contains an entry for this variant (Variation ID: 439755). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2005 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 16, 2018 | The GIF c.79+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in four studies in which it is found in a total of 13 individuals with intrinsic factor deficiency, megaloblastic anemia and cobalamin malabsorption. The variant was reported in a homozygous state in four individuals, including three unrelated cases and in a compound heterozygous state in nine individuals, six of whom were unrelated (Tanner et al. 2005; Overgaard et al. 2010; Tanner et al. 2012; Ferrand et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the evidence and the potential impact of splice donor variants, the c.79+1G>A variant is classified as pathogenic for intrinsic factor deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jan 16, 2020 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 16, 2020 | The CBLIF c.79+1G>A variant (rs147785187) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with intrinsic factor deficiency (Ferrand 2015, Overgaard 2010, Tanner 2005, Tanner 2012). This variant is reported in ClinVar (Variation ID: 439755), and is found in the general population with an overall allele frequency of 0.019% (54/282620 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 1, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Ferrand A et al. Biochemical and Hematologic Manifestations of Gastric Intrinsic Factor (GIF) Deficiency: A Treatable Cause of B12 Deficiency in the Old Order Mennonite Population of Southwestern Ontario. JIMD Rep. 2015;18:69-77. Overgaard UM et al. Vitamin B12 deficiency in a 15-year old boy due to mutations in the intrinsic factor gene, GIF. Br J Haematol. 2010 Aug;150(3):369-71. Tanner SM et al. Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4130-3. Tanner SM et al. Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. Orphanet J Rare Dis. 2012 Aug 28;7:56. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 08, 2018 | - - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jun 03, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PM3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at