rs199655061

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-59831762-C-G
• chr11-59831762-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005142.3(CBLIF):​c.1108G>C​(p.Val370Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,452,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. V370I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CBLIF NM_005142.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.379062).

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>C	p.Val370Leu	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>C	p.Val370Leu	missense	Exon 8 of 9	ENSP00000257248.2	P27352-1
	CBLIF	ENST00000525058.5	TSL:2	n.*1075G>C		non_coding_transcript_exon	Exon 8 of 9	ENSP00000433196.1	E9PM21
	CBLIF	ENST00000533067.1	TSL:3	n.155G>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251396 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1452762 Hom.: 0 Cov.: 27 AF XY: 0.00000691 AC XY: 5 AN XY: 723326

African (AFR) AF: 0.0000300 AC: 1 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: 0.00 AC: 0 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: 0.00000815 AC: 9 AN: 1103726

Other (OTH) AF: 0.00 AC: 0 AN: 60076

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.96
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.28
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.070
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.049	D
Vest4		0.60
MutPred		0.37		Gain of catalytic residue at V370 (P = 0.1839)
MVP		0.15
MPC		0.14
ClinPred		0.20	T
GERP RS		1.1
gMVP		0.78
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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;