rs2867802

Positions:

• chr11-59835891-G-A
• chr11-59835891-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005142.3(CBLIF):​c.990C>T​(p.Asn330=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 1,614,002 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (497 hom.)
• Consequence: CBLIF NM_005142.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.848

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-59835891-G-A is Benign according to our data. Variant chr11-59835891-G-A is described in ClinVar as [Benign]. Clinvar id is 305031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.848 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.064 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBLIF	NM_005142.3	c.990C>T	p.Asn330=	synonymous_variant	7/9	ENST00000257248.3
CBLIF	XM_011544939.4	c.948C>T	p.Asn316=	synonymous_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBLIF	ENST00000257248.3	c.990C>T	p.Asn330=	synonymous_variant	7/9	1	NM_005142.3	P1
CBLIF	ENST00000533067.1	n.37C>T		non_coding_transcript_exon_variant	1/2	3
CBLIF	ENST00000533847.1	n.642C>T		non_coding_transcript_exon_variant	3/3	5
CBLIF	ENST00000525058.5	c.*957C>T		3_prime_UTR_variant, NMD_transcript_variant	7/9	2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1560 AN: 152142 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0675

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0594

Gnomad SAS AF: 0.00748

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0216 AC: 5432 AN: 251384 Hom.: 317 AF XY: 0.0166 AC XY: 2251 AN XY: 135856

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.0552

Gnomad SAS exome AF: 0.00379

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.00652 AC: 9528 AN: 1461742 Hom.: 497 Cov.: 32 AF XY: 0.00577 AC XY: 4197 AN XY: 727170

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.0737

Gnomad4 SAS exome AF: 0.00384

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000588

Gnomad4 OTH exome AF: 0.00722

GnomAD4 genome AF: 0.0102 AC: 1557 AN: 152260 Hom.: 51 Cov.: 32 AF XY: 0.0113 AC XY: 839 AN XY: 74438

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.0674

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.0593

Gnomad4 SAS AF: 0.00727

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00763 Hom.: 41

Bravo AF: 0.0158

Asia WGS AF: 0.0470 AC: 163 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary intrinsic factor deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.41
DANN	Benign	0.47

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

LitVar

Other links and lift over

dbSNP: rs2867802; hg19: chr11-59603364; COSMIC: COSV57238365;