11-59843998-G-C

Variant names:

• chr11-59843998-G-C
• rs121434322
• NM_005142.3:c.137C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_005142.3(CBLIF):​c.137C>G​(p.Ser46Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S46L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CBLIF NM_005142.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58
• Publications: 0 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-59843998-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLIF	NM_005142.3	MANE Select	c.137C>G	p.Ser46Trp	missense	Exon 2 of 9	NP_005133.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLIF	ENST00000257248.3	TSL:1 MANE Select	c.137C>G	p.Ser46Trp	missense	Exon 2 of 9	ENSP00000257248.2
	CBLIF	ENST00000525058.5	TSL:2	n.*104C>G		non_coding_transcript_exon	Exon 2 of 9	ENSP00000433196.1
	CBLIF	ENST00000532070.1	TSL:2	n.183C>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.58	T
PhyloP100		3.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Vest4		0.61
MutPred		0.75		Loss of disorder (P = 0.0039)
MVP		0.55
MPC		0.67
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.91
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs121434322; hg19: chr11-59611471;