rs150884181

Variant names:

• chr11-59843108-A-G
• rs150884181
• NM_005142.3:c.290T>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.52

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 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: {Benign=4, Uncertain_significance=1}. 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 rank	MANE	Protein	UniProt
CBLIF	NM_005142.3	c.290T>C	p.Met97Thr	missense_variant	Exon 3 of 9	ENST00000257248.3	NP_005133.2
CBLIF	XM_011544939.4	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	Appris	UniProt
CBLIF	ENST00000257248.3	c.290T>C	p.Met97Thr	missense_variant	Exon 3 of 9	1	NM_005142.3	ENSP00000257248.2
CBLIF	ENST00000525058.5	n.*257T>C		non_coding_transcript_exon_variant	Exon 3 of 9	2		ENSP00000433196.1
CBLIF	ENST00000532070.1	n.336T>C		non_coding_transcript_exon_variant	Exon 3 of 3	2
CBLIF	ENST00000525058.5	n.*257T>C		3_prime_UTR_variant	Exon 3 of 9	2		ENSP00000433196.1

Frequencies

GnomAD3 genomes AF: 0.00796 AC: 1212 AN: 152192 Hom.: 17 Cov.: 32

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.: 32 AF XY: 0.00886 AC XY: 1203 AN XY: 135786

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.: 30 AF XY: 0.00970 AC XY: 7048 AN XY: 726966

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.: 17 Cov.: 32 AF XY: 0.00926 AC XY: 690 AN XY: 74492

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.: 11

Bravo AF: 0.00521

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00990 AC: 85

ExAC AF: 0.00890 AC: 1080

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00960

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary intrinsic factor deficiency Uncertain:1 Benign:2

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 “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. 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 -

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. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.78	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Vest4		0.77
MVP		0.50
MPC		0.62
ClinPred		0.024	T
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

Other links and lift over

dbSNP: rs150884181; hg19: chr11-59610581; COSMIC: COSV57239576; COSMIC: COSV57239576;