rs150884181

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

hereditary intrinsic factor deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

CBLIF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 305040.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLIF	NM_005142.3 link	c.290T>C	p.Met97Thr	missense_variant	Exon 3 of 9	ENST00000257248.3	NP_005133.2	P27352-1
CBLIF	XM_011544939.4 link	c.290T>C	p.Met97Thr	missense_variant	Exon 3 of 9		XP_011543241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CBLIF	ENST00000257248.3 link	c.290T>C	p.Met97Thr	missense_variant	Exon 3 of 9	1	NM_005142.3	ENSP00000257248.2	P27352-1
CBLIF	ENST00000525058.5 link	n.*257T>C		non_coding_transcript_exon_variant	Exon 3 of 9	2		ENSP00000433196.1	E9PM21
CBLIF	ENST00000532070.1 link	n.336T>C		non_coding_transcript_exon_variant	Exon 3 of 3	2
CBLIF	ENST00000525058.5 link	n.*257T>C		3_prime_UTR_variant	Exon 3 of 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

GnomAD2 exomes

AF:

0.00900

AC:

2262

AN:

251224

AF XY:

0.00886

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 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

African (AFR)

AF:

0.00140

AC:

AN:

33464

American (AMR)

AF:

0.00195

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00658

AC:

172

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00267

AC:

230

AN:

86244

European-Finnish (FIN)

AF:

0.0315

AC:

1685

AN:

53410

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0107

AC:

11928

AN:

1111426

Other (OTH)

AF:

0.00611

AC:

369

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

677

1354

2031

2708

3385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

452

904

1356

1808

2260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00796

AC:

1212

AN:

152310

Hom.:

Cov.:

AF XY:

0.00926

AC XY:

690

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00192

AC:

AN:

41574

American (AMR)

AF:

0.000850

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0406

AC:

431

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00959

AC:

652

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

130

194

259

324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00872

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

Hereditary intrinsic factor deficiency

Uncertain:1Benign:2

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CBLIF c.290T>C p.Met97Thr variant (rs150884181, ClinVar Variation ID: 305040) 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 â€œsecretorâ€ 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. 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 -

not provided

Benign:2

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CBLIF: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CBLIF-related disorder

Benign:1

Apr 29, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

4.5

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

Mutation Taster

=52/48

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over