11-59831762-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005142.3(CBLIF):ā€‹c.1108G>Cā€‹(p.Val370Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,452,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V370I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000069 ( 0 hom. )

Consequence

CBLIF
NM_005142.3 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.284
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.379062).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CBLIFNM_005142.3 linkuse as main transcriptc.1108G>C p.Val370Leu missense_variant 8/9 ENST00000257248.3
CBLIFXM_011544939.4 linkuse as main transcriptc.1066G>C p.Val356Leu missense_variant 8/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CBLIFENST00000257248.3 linkuse as main transcriptc.1108G>C p.Val370Leu missense_variant 8/91 NM_005142.3 P1P27352-1
CBLIFENST00000533067.1 linkuse as main transcriptn.155G>C non_coding_transcript_exon_variant 2/23
CBLIFENST00000525058.5 linkuse as main transcriptc.*1075G>C 3_prime_UTR_variant, NMD_transcript_variant 8/92

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251396
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000688
AC:
10
AN:
1452762
Hom.:
0
Cov.:
27
AF XY:
0.00000691
AC XY:
5
AN XY:
723326
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
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:
0.00000815
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 30, 2021The c.1108G>C (p.V370L) alteration is located in exon 8 (coding exon 8) of the GIF gene. This alteration results from a G to C substitution at nucleotide position 1108, causing the valine (V) at amino acid position 370 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
12
DANN
Benign
0.96
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.086
N
LIST_S2
Benign
0.71
T
M_CAP
Benign
0.0092
T
MetaRNN
Benign
0.38
T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.95
N
REVEL
Benign
0.070
Sift
Uncertain
0.017
D
Sift4G
Uncertain
0.049
D
Vest4
0.60
MutPred
0.37
Gain of catalytic residue at V370 (P = 0.1839);
MVP
0.15
MPC
0.14
ClinPred
0.20
T
GERP RS
1.1
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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.

Other links and lift over

dbSNP: rs199655061; hg19: chr11-59599235; API