rs150884181
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_005142.3(CBLIF):c.290T>C(p.Met97Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00975 in 1,613,536 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0080 ( 17 hom., cov: 32)
Exomes 𝑓: 0.0099 ( 119 hom. )
Consequence
CBLIF
NM_005142.3 missense
NM_005142.3 missense
Scores
2
9
5
Clinical Significance
Conservation
PhyloP100: 4.52
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 Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.015157074).
BP6
?
Variant 11-59843108-A-G is Benign according to our data. Variant chr11-59843108-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305040.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=1}. Variant chr11-59843108-A-G is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00796 (1212/152310) while in subpopulation NFE AF= 0.00959 (652/68014). AF 95% confidence interval is 0.00898. There are 17 homozygotes in gnomad4. There are 690 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 17 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBLIF | NM_005142.3 | c.290T>C | p.Met97Thr | missense_variant | 3/9 | ENST00000257248.3 | |
CBLIF | XM_011544939.4 | c.290T>C | p.Met97Thr | missense_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBLIF | ENST00000257248.3 | c.290T>C | p.Met97Thr | missense_variant | 3/9 | 1 | NM_005142.3 | P1 | |
CBLIF | ENST00000532070.1 | n.336T>C | non_coding_transcript_exon_variant | 3/3 | 2 | ||||
CBLIF | ENST00000525058.5 | c.*257T>C | 3_prime_UTR_variant, NMD_transcript_variant | 3/9 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00796 AC: 1212AN: 152192Hom.: 17 Cov.: 32
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GnomAD3 exomes AF: 0.00900 AC: 2262AN: 251224Hom.: 32 AF XY: 0.00886 AC XY: 1203AN XY: 135786
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GnomAD4 exome AF: 0.00994 AC: 14520AN: 1461226Hom.: 119 Cov.: 30 AF XY: 0.00970 AC XY: 7048AN XY: 726966
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GnomAD4 genome ? AF: 0.00796 AC: 1212AN: 152310Hom.: 17 Cov.: 32 AF XY: 0.00926 AC XY: 690AN XY: 74492
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 09, 2023 | The CBLIF c.290T>C p.Met97Thr variant (rs150884181) has been observed in trans opposite the pathogenic c.79+1G>A variant in two individuals recruited for suspicion of inherited VB12 deficiency (Overgaard 2010 and Tanner 2012). Additionally, individuals heterozygous for the p.Met97Thr variant and harboring the FUT2 polymorphic “secretor” genotype (rs601338 GG/GA) have been shown to have an increased risk for VB12 deficiency (Chery 2013) and neural tube defects (NTDs; Gueant-Rodriguez 2018). Functional studies have also shown that CBLIF protein harboring the p.Met97Thr variant has a reduced ability to bind VB12 (Chery 2013). However, the p.Met97Thr variant is common in the general population and is specifically found in the Finnish population with an allele frequency of 3.6% (909/25108 alleles, including 24 homozygotes) in the Genome Aggregation Database. This suggests that the p.Met97Thr variant may be a contributing risk factor in elevated VB12, but is unlikely to have a strong, monogenic effect. Additionally, at least two laboratories call this variant Benign in ClinVar (Variation ID: 305040). Due to conflicting information, the clinical significance of the p.Met97Thr variant is uncertain at this time. References: Gueant-Rodriguez RM et al. Association of combined GIF290T>C heterozygous mutation/FUT2 secretor variant with neural tube defects. Clin Genet. 2018 Jan;93(1):191-193. PMID: 28742214. Chery C, et al. Gastric intrinsic factor deficiency with combined GIF heterozygous mutations and FUT2 secretor variant. Biochimie. 2013 May;95(5):995-100. PMID: 23402911. 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. PMID: 20408840 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. PMID: 22929189 - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | CBLIF: BS1, BS2 - |
Hereditary intrinsic factor deficiency Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
CBLIF-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 29, 2020 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at