rs765896727

Positions:

• chr11-59843948-GATTC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005142.3(CBLIF):​c.183_186del​(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:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CBLIF NM_005142.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.14

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-59843948-GATTC-G is Pathogenic according to our data. Variant chr11-59843948-GATTC-G is described in ClinVar as [Pathogenic]. Clinvar id is 566919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBLIF	NM_005142.3	c.183_186del	p.Met61IlefsTer8	frameshift_variant	2/9	ENST00000257248.3	NP_005133.2
CBLIF	XM_011544939.4	c.183_186del	p.Met61IlefsTer8	frameshift_variant	2/9		XP_011543241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBLIF	ENST00000257248.3	c.183_186del	p.Met61IlefsTer8	frameshift_variant	2/9	1	NM_005142.3	ENSP00000257248	P1
CBLIF	ENST00000532070.1	n.229_232del		non_coding_transcript_exon_variant	2/3	2
CBLIF	ENST00000525058.5	c.*150_*153del		3_prime_UTR_variant, NMD_transcript_variant	2/9	2		ENSP00000433196

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 251258 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135782

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461362 Hom.: 0 AF XY: 0.0000206 AC XY: 15 AN XY: 727012

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74450

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000181

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary intrinsic factor deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 05, 2023	ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 moderated, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2005	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2023	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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs765896727; hg19: chr11-59611421;