11-59843108-A-G

Position:

chr11-59843108-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005142.3(CBLIF):c.290T>C(p.Met97Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00975 in 1,613,536 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0080 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0099 ( 119 hom. )

Consequence

CBLIF
NM_005142.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.52

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:

CBLIF (HGNC:):

CBLIF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015157074).

BP6

Variant 11-59843108-A-G is Benign according to our data. Variant chr11-59843108-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305040.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}. Variant chr11-59843108-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00796 (1212/152310) while in subpopulation NFE AF= 0.00959 (652/68014). AF 95% confidence interval is 0.00898. There are 17 homozygotes in gnomad4. There are 690 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBLIF	NM_005142.3 linkuse as main transcript	c.290T>C	p.Met97Thr	missense_variant	3/9	ENST00000257248.3	NP_005133.2	P27352-1
CBLIF	XM_011544939.4 linkuse as main transcript	c.290T>C	p.Met97Thr	missense_variant	3/9		XP_011543241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CBLIF	ENST00000257248.3 linkuse as main transcript	c.290T>C	p.Met97Thr	missense_variant	3/9	1	NM_005142.3	ENSP00000257248.2	P27352-1
CBLIF	ENST00000525058.5 linkuse as main transcript	n.*257T>C		non_coding_transcript_exon_variant	3/9	2		ENSP00000433196.1	E9PM21
CBLIF	ENST00000532070.1 linkuse as main transcript	n.336T>C		non_coding_transcript_exon_variant	3/3	2
CBLIF	ENST00000525058.5 linkuse as main transcript	n.*257T>C		3_prime_UTR_variant	3/9	2		ENSP00000433196.1	E9PM21

Frequencies

GnomAD3 genomes

AF:

0.00796

AC:

1212

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0406

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00959

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00900

AC:

2262

AN:

251224

Hom.:

AF XY:

0.00886

AC XY:

1203

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00486

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00238

Gnomad FIN exome

AF:

0.0354

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00783

GnomAD4 exome

AF:

0.00994

AC:

14520

AN:

1461226

Hom.:

119

Cov.:

AF XY:

0.00970

AC XY:

7048

AN XY:

726966

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00195

Gnomad4 ASJ exome

AF:

0.00658

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00267

Gnomad4 FIN exome

AF:

0.0315

Gnomad4 NFE exome

AF:

0.0107

Gnomad4 OTH exome

AF:

0.00611

GnomAD4 genome

AF:

0.00796

AC:

1212

AN:

152310

Hom.:

Cov.:

AF XY:

0.00926

AC XY:

690

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00192

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.0406

Gnomad4 NFE

AF:

0.00959

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00880

Hom.:

Bravo

AF:

0.00521

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00990

AC:

ExAC

AF:

0.00890

AC:

1080

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00682

EpiControl

AF:

0.00960

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CBLIF: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	The CBLIF c.290T>C p.Met97Thr variant (rs150884181) has been observed in trans opposite the pathogenic c.79+1G>A variant in two individuals recruited for suspicion of inherited VB12 deficiency (Overgaard 2010 and Tanner 2012). Additionally, individuals heterozygous for the p.Met97Thr variant and harboring the FUT2 polymorphic “secretor” genotype (rs601338 GG/GA) have been shown to have an increased risk for VB12 deficiency (Chery 2013) and neural tube defects (NTDs; Gueant-Rodriguez 2018). Functional studies have also shown that CBLIF protein harboring the p.Met97Thr variant has a reduced ability to bind VB12 (Chery 2013). However, the p.Met97Thr variant is common in the general population and is specifically found in the Finnish population with an allele frequency of 3.6% (909/25108 alleles, including 24 homozygotes) in the Genome Aggregation Database. This suggests that the p.Met97Thr variant may be a contributing risk factor in elevated VB12, but is unlikely to have a strong, monogenic effect. Additionally, at least two laboratories call this variant Benign in ClinVar (Variation ID: 305040). Due to conflicting information, the clinical significance of the p.Met97Thr variant is uncertain at this time. References: Gueant-Rodriguez RM et al. Association of combined GIF290T>C heterozygous mutation/FUT2 secretor variant with neural tube defects. Clin Genet. 2018 Jan;93(1):191-193. PMID: 28742214. Chery C, et al. Gastric intrinsic factor deficiency with combined GIF heterozygous mutations and FUT2 secretor variant. Biochimie. 2013 May;95(5):995-100. PMID: 23402911. Overgaard UM, et al. Vitamin B12 deficiency in a 15-year old boy due to mutations in the intrinsic factor gene, GIF. Br J Haematol. 2010 Aug;150(3):369-71. PMID: 20408840 Tanner SM, et al. Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. Orphanet J Rare Dis. 2012 Aug 28;7:56. PMID: 22929189 -

Hereditary intrinsic factor deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

CBLIF-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.67

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.78

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.35

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Vest4

0.77

MVP

0.50

MPC

0.62

ClinPred

0.024

GERP RS

6.1

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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