rs35211634

chr11-59845386-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005142.3(CBLIF):c.68A>G(p.Gln23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 1,611,514 control chromosomes in the GnomAD database, including 3,993 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (1103 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2890 hom.)
• Consequence: CBLIF NM_005142.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -2.89

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009813279).
• BP6: Variant 11-59845386-T-C is Benign according to our data. Variant chr11-59845386-T-C is described in ClinVar as [Benign]. Clinvar id is 1742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-59845386-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBLIF	NM_005142.3	c.68A>G	p.Gln23Arg	missense_variant	1/9	ENST00000257248.3
CBLIF	XM_011544939.4	c.68A>G	p.Gln23Arg	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBLIF	ENST00000257248.3	c.68A>G	p.Gln23Arg	missense_variant	1/9	1	NM_005142.3	P1
CBLIF	ENST00000532070.1	n.114A>G		non_coding_transcript_exon_variant	1/3	2
CBLIF	ENST00000525058.5	c.68A>G	p.Gln23Arg	missense_variant, NMD_transcript_variant	1/9	2

Frequencies

GnomAD3 genomes AF: 0.0950 AC: 14442 AN: 151996 Hom.: 1094 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0428

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.0363

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.0708

GnomAD3 exomes AF: 0.0589 AC: 14807 AN: 251222 Hom.: 727 AF XY: 0.0550 AC XY: 7468 AN XY: 135766

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.0261

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.0396

Gnomad SAS exome AF: 0.0372

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.0507

Gnomad OTH exome AF: 0.0441

GnomAD4 exome AF: 0.0544 AC: 79327 AN: 1459400 Hom.: 2890 Cov.: 29 AF XY: 0.0532 AC XY: 38661 AN XY: 726190

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.0266

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.0290

Gnomad4 SAS exome AF: 0.0369

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.0514

Gnomad4 OTH exome AF: 0.0552

GnomAD4 genome AF: 0.0953 AC: 14494 AN: 152114 Hom.: 1103 Cov.: 32 AF XY: 0.0958 AC XY: 7129 AN XY: 74386

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.0426

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.0362

Gnomad4 SAS AF: 0.0356

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.0500

Gnomad4 OTH AF: 0.0705

Alfa AF: 0.0542 Hom.: 752

Bravo AF: 0.0962

TwinsUK AF: 0.0453 AC: 168

ALSPAC AF: 0.0509 AC: 196

ESP6500AA AF: 0.197 AC: 866

ESP6500EA AF: 0.0481 AC: 413

ExAC AF: 0.0607 AC: 7370

Asia WGS AF: 0.0640 AC: 222 AN: 3478

EpiCase AF: 0.0431

EpiControl AF: 0.0433

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

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

- -

Intrinsic factor deficiency, congenital, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 15, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.0020
Dann	Benign	0.20
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	0.84	T
Vest4		0.018
MPC		0.13
ClinPred		0.0061	T
GERP RS		-4.4
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35211634; hg19: chr11-59612859; COSMIC: COSV57239149; COSMIC: COSV57239149;