rs35211634

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005142.3(CBLIF):c.68A>G(p.Gln23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 1,611,514 control chromosomes in the GnomAD database, including 3,993 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.095 ( 1103 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2890 hom. )

Consequence

CBLIF
NM_005142.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -2.89

Publications

20 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009813279).

BP6

Variant 11-59845386-T-C is Benign according to our data. Variant chr11-59845386-T-C is described in ClinVar as Benign. ClinVar VariationId is 1742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLIF	NM_005142.3 link	c.68A>G	p.Gln23Arg	missense_variant	Exon 1 of 9	ENST00000257248.3	NP_005133.2	P27352-1
CBLIF	XM_011544939.4 link	c.68A>G	p.Gln23Arg	missense_variant	Exon 1 of 9		XP_011543241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CBLIF	ENST00000257248.3 link	c.68A>G	p.Gln23Arg	missense_variant	Exon 1 of 9	1	NM_005142.3	ENSP00000257248.2	P27352-1
CBLIF	ENST00000525058.5 link	n.68A>G		non_coding_transcript_exon_variant	Exon 1 of 9	2		ENSP00000433196.1	E9PM21
CBLIF	ENST00000532070.1 link	n.114A>G		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0950

AC:

14442

AN:

151996

Hom.:

1094

Cov.:

show subpopulations

Gnomad AFR

AF:

0.208

Gnomad AMI

AF:

0.0418

Gnomad AMR

AF:

0.0428

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.0363

Gnomad SAS

AF:

0.0356

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0501

Gnomad OTH

AF:

0.0708

GnomAD2 exomes

AF:

0.0589

AC:

14807

AN:

251222

AF XY:

0.0550

show subpopulations

Gnomad AFR exome

AF:

0.213

Gnomad AMR exome

AF:

0.0261

Gnomad ASJ exome

AF:

0.0164

Gnomad EAS exome

AF:

0.0396

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0507

Gnomad OTH exome

AF:

0.0441

GnomAD4 exome

AF:

0.0544

AC:

79327

AN:

1459400

Hom.:

2890

Cov.:

AF XY:

0.0532

AC XY:

38661

AN XY:

726190

show subpopulations

African (AFR)

AF:

0.216

AC:

7224

AN:

33412

American (AMR)

AF:

0.0266

AC:

1187

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0175

AC:

458

AN:

26112

East Asian (EAS)

AF:

0.0290

AC:

1152

AN:

39684

South Asian (SAS)

AF:

0.0369

AC:

3180

AN:

86210

European-Finnish (FIN)

AF:

0.105

AC:

5615

AN:

53360

Middle Eastern (MID)

AF:

0.0205

AC:

118

AN:

5758

European-Non Finnish (NFE)

AF:

0.0514

AC:

57062

AN:

1109846

Other (OTH)

AF:

0.0552

AC:

3331

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

3710

7421

11131

14842

18552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2188

4376

6564

8752

10940

<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:

0.0953

AC:

14494

AN:

152114

Hom.:

1103

Cov.:

AF XY:

0.0958

AC XY:

7129

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.208

AC:

8642

AN:

41470

American (AMR)

AF:

0.0426

AC:

651

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3468

East Asian (EAS)

AF:

0.0362

AC:

187

AN:

5160

South Asian (SAS)

AF:

0.0356

AC:

172

AN:

4826

European-Finnish (FIN)

AF:

0.110

AC:

1168

AN:

10588

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0500

AC:

3403

AN:

68002

Other (OTH)

AF:

0.0705

AC:

149

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

615

1230

1845

2460

3075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.0605

Hom.:

1854

Bravo

AF:

0.0962

TwinsUK

AF:

0.0453

AC:

168

ALSPAC

AF:

0.0509

AC:

196

ESP6500AA

AF:

0.197

AC:

866

ESP6500EA

AF:

0.0481

AC:

413

ExAC

AF:

0.0607

AC:

7370

Asia WGS

AF:

0.0640

AC:

222

AN:

3478

EpiCase

AF:

0.0431

EpiControl

AF:

0.0433

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary intrinsic factor deficiency

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intrinsic factor deficiency, congenital, susceptibility to

Other:1

Mar 15, 2005

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.0020

(source)

DANN

Benign

0.20

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.20

MetaRNN

Benign

0.0098

MetaSVM

Benign

-0.93

PhyloP100

-2.9

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.37

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

0.84

Vest4

0.018

MPC

0.13

ClinPred

0.0061

GERP RS

-4.4

PromoterAI

0.019

Neutral

(source)

gMVP

0.27

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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