chr11-59831762-C-T

Variant names:

• chr11-59831762-C-T
• rs199655061
• NM_005142.3:c.1108G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005142.3(CBLIF):​c.1108G>A​(p.Val370Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,604,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V370L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CBLIF NM_005142.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.284
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03400156).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005142.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLIF	NM_005142.3	MANE Select	c.1108G>A	p.Val370Ile	missense	Exon 8 of 9	NP_005133.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLIF	ENST00000257248.3	TSL:1 MANE Select	c.1108G>A	p.Val370Ile	missense	Exon 8 of 9	ENSP00000257248.2	P27352-1
	CBLIF	ENST00000525058.5	TSL:2	n.*1075G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000433196.1	E9PM21
	CBLIF	ENST00000533067.1	TSL:3	n.155G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251396 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000207 AC: 30 AN: 1452762 Hom.: 0 Cov.: 27 AF XY: 0.0000221 AC XY: 16 AN XY: 723326

African (AFR) AF: 0.00 AC: 0 AN: 33294

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000190 AC: 21 AN: 1103726

Other (OTH) AF: 0.0000166 AC: 1 AN: 60076

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151998 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74272

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000251 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary intrinsic factor deficiency (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.8
DANN	Benign	0.51
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.28
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.012
Sift	Benign	0.60	T
Sift4G	Benign	0.68	T
Vest4		0.23
MutPred		0.31		Gain of catalytic residue at S372 (P = 0.225)
MVP		0.14
MPC		0.10
ClinPred		0.021	T
GERP RS		1.1
gMVP		0.59
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs199655061; hg19: chr11-59599235;