Variant chr11-59843948-GATTC-G details in Genebe, Genetics Data Aggregator

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

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CBLIF
NM_005142.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.14

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]

CBLIF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
CBLIF	NM_005142.3 link	c.183_186delGAAT	p.Met61IlefsTer8	frameshift_variant	Exon 2 of 9	ENST00000257248.3	NP_005133.2	P27352-1
CBLIF	XM_011544939.4 link	c.183_186delGAAT	p.Met61IlefsTer8	frameshift_variant	Exon 2 of 9		XP_011543241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CBLIF	ENST00000257248.3 link	c.183_186delGAAT	p.Met61IlefsTer8	frameshift_variant	Exon 2 of 9	1	NM_005142.3	ENSP00000257248.2	P27352-1
CBLIF	ENST00000525058.5 link	n.150_153delGAAT		non_coding_transcript_exon_variant	Exon 2 of 9	2		ENSP00000433196.1	E9PM21
CBLIF	ENST00000532070.1 link	n.229_232delGAAT		non_coding_transcript_exon_variant	Exon 2 of 3	2
CBLIF	ENST00000525058.5 link	n.150_153delGAAT		3_prime_UTR_variant	Exon 2 of 9	2		ENSP00000433196.1	E9PM21

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

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:

AN:

251258

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135782

show subpopulations

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:

AN:

1461362

Hom.:

AF XY:

0.0000206

AC XY:

AN XY:

727012

show subpopulations

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:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74450

show subpopulations

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.:

Bravo

AF:

0.000181

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary intrinsic factor deficiency

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 22, 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, 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 -

not provided

Pathogenic:2

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) -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over