NM_005142.3:c.435_437delGAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBS1BS2

The NM_005142.3(CBLIF):c.435_437delGAA(p.Lys145del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,614,012 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 3 hom. )

Consequence

CBLIF
NM_005142.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 1.39

Publications

0 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 -15 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_005142.3. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 11-59842516-GTTC-G is Benign according to our data. Variant chr11-59842516-GTTC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 208192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0016 (244/152346) while in subpopulation AMR AF = 0.0049 (75/15298). AF 95% confidence interval is 0.00401. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLIF	NM_005142.3 link	c.435_437delGAA	p.Lys145del	disruptive_inframe_deletion	Exon 4 of 9	ENST00000257248.3	NP_005133.2	P27352-1
CBLIF	XM_011544939.4 link	c.435_437delGAA	p.Lys145del	disruptive_inframe_deletion	Exon 4 of 9		XP_011543241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CBLIF	ENST00000257248.3 link	c.435_437delGAA	p.Lys145del	disruptive_inframe_deletion	Exon 4 of 9	1	NM_005142.3	ENSP00000257248.2	P27352-1
CBLIF	ENST00000525058.5 link	n.402_404delGAA		non_coding_transcript_exon_variant	Exon 4 of 9	2		ENSP00000433196.1	E9PM21
CBLIF	ENST00000532070.1 link	n.925_927delGAA		non_coding_transcript_exon_variant	Exon 3 of 3	2
CBLIF	ENST00000525058.5 link	n.402_404delGAA		3_prime_UTR_variant	Exon 4 of 9	2		ENSP00000433196.1	E9PM21

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00223

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00128

AC:

321

AN:

251080

AF XY:

0.00127

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00223

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00216

AC:

3151

AN:

1461666

Hom.:

AF XY:

0.00219

AC XY:

1594

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33474

American (AMR)

AF:

0.00143

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.00265

AC:

2946

AN:

1111982

Other (OTH)

AF:

0.00179

AC:

108

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

158

315

473

630

788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00160

AC:

244

AN:

152346

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41592

American (AMR)

AF:

0.00490

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00223

AC:

152

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000312

Hom.:

Bravo

AF:

0.00145

EpiCase

AF:

0.00196

EpiControl

AF:

0.00166

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary intrinsic factor deficiency

Benign:1Other:1

Inserm U 954, Faculté de Médecine de Nancy

Significance:not provided

Review Status:no classification provided

Collection Method:not provided

- -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 19, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CBLIF c.435_437delGAA (p.Lys145del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in CBLIF causing Intrinsic Factor Deficiency phenotype (0.0011). c.435_437delGAA has been observed in individuals affected with CBLIF related disorders in heterozygous state (Chery_2013, Abdrabo_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Intrinsic Factor Deficiency. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Chery_2013). ClinVar contains an entry for this variant (Variation ID: 208192). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=71/29

polymorphism

(source)

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

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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