11-59831688-AG-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_005142.3(CBLIF):c.1181del(p.Pro394LeufsTer2) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CBLIF NM_005142.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0582 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBLIF	NM_005142.3	c.1181del	p.Pro394LeufsTer2	frameshift_variant	8/9	ENST00000257248.3
CBLIF	XM_011544939.4	c.1139del	p.Pro380LeufsTer2	frameshift_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBLIF	ENST00000257248.3	c.1181del	p.Pro394LeufsTer2	frameshift_variant	8/9	1	NM_005142.3	P1
CBLIF	ENST00000533067.1	n.228del		non_coding_transcript_exon_variant	2/2	3
CBLIF	ENST00000525058.5	c.*1148del		3_prime_UTR_variant, NMD_transcript_variant	8/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary intrinsic factor deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 04, 2018

This sequence change results in a premature translational stop signal in the GIF gene (p.Pro394Leufs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt/delete the last 24 amino acids of the GIF protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GIF-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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

Other links and lift over

dbSNP: rs1565206584; hg19: chr11-59599161;