chr11-59843948-GATTC-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005142.3(CBLIF):c.183_186delGAAT(p.Met61IlefsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000477 in 1,613,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005142.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CBLIF | ENST00000257248.3 | c.183_186delGAAT | p.Met61IlefsTer8 | frameshift_variant | Exon 2 of 9 | 1 | NM_005142.3 | ENSP00000257248.2 | ||
CBLIF | ENST00000525058.5 | n.*150_*153delGAAT | non_coding_transcript_exon_variant | Exon 2 of 9 | 2 | ENSP00000433196.1 | ||||
CBLIF | ENST00000532070.1 | n.229_232delGAAT | non_coding_transcript_exon_variant | Exon 2 of 3 | 2 | |||||
CBLIF | ENST00000525058.5 | n.*150_*153delGAAT | 3_prime_UTR_variant | Exon 2 of 9 | 2 | ENSP00000433196.1 |
Frequencies
GnomAD3 genomes AF: 0.000230 AC: 35AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251258Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135782
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461362Hom.: 0 AF XY: 0.0000206 AC XY: 15AN XY: 727012
GnomAD4 genome AF: 0.000230 AC: 35AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74450
ClinVar
Submissions by phenotype
Hereditary intrinsic factor deficiency Pathogenic:3
ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 moderated, PP4 -
This sequence change creates a premature translational stop signal (p.Met61Ilefs*8) in the GIF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GIF are known to be pathogenic (PMID: 14576042, 22929189). This variant is present in population databases (rs765896727, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with intrinsic factor deficiency (PMID: 14576042, 19036097, 22854512, 22929189). ClinVar contains an entry for this variant (Variation ID: 566919). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:2
The c.183_186delGAAT; p.Met61fs was found homozygote in an 11 year old African American female with megaloblastic anemia and cobalamin deficiency, who inherited the variant from a heterozygote mother (Yassin, 2004). This variant was further observed in three patients of African descent, who were diagnosed with juvenile cobalamin deficiency, whereby parental haplotype analysis indicated a likely founder event of the deletion in the Sub-Saharan West-African lineage (Ament, 2009). Consistent with this study, the c.183_186delGAAT variant is identified on 17 out of 276,970 chromosomes, 14 from the African population, with an overall frequency of 0.006 percent listed in the Genome Aggregation Database (gnomAD). This variant is also reported to the ClinVar database with a pathogenic classification (Variation ID: 1743). Altogether the c.183_186delGAAT is pathogenic. -
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 14576042, 22929189, 19036097, 22854512) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at