NM_005142.3:c.290T>C

Variant names:

• chr11-59843108-A-G
• rs150884181
• NM_005142.3:c.290T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005142.3(CBLIF):​c.290T>C​(p.Met97Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00975 in 1,613,536 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0080 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (119 hom.)
• Consequence: CBLIF NM_005142.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.52
• Publications: 10 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015157074).
• BP6: Variant 11-59843108-A-G is Benign according to our data. Variant chr11-59843108-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305040.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00796 (1212/152310) while in subpopulation NFE AF = 0.00959 (652/68014). AF 95% confidence interval is 0.00898. There are 17 homozygotes in GnomAd4. There are 690 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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.290T>C	p.Met97Thr	missense	Exon 3 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.290T>C	p.Met97Thr	missense	Exon 3 of 9	ENSP00000257248.2
	CBLIF	ENST00000525058.5	TSL:2	n.*257T>C		non_coding_transcript_exon	Exon 3 of 9	ENSP00000433196.1
	CBLIF	ENST00000532070.1	TSL:2	n.336T>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00796 AC: 1212 AN: 152192 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00959

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00900 AC: 2262 AN: 251224 AF XY: 0.00886

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0354

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00994 AC: 14520 AN: 1461226 Hom.: 119 Cov.: 30 AF XY: 0.00970 AC XY: 7048 AN XY: 726966

African (AFR) AF: 0.00140 AC: 47 AN: 33464

American (AMR) AF: 0.00195 AC: 87 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00658 AC: 172 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00267 AC: 230 AN: 86244

European-Finnish (FIN) AF: 0.0315 AC: 1685 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0107 AC: 11928 AN: 1111426

Other (OTH) AF: 0.00611 AC: 369 AN: 60376

GnomAD4 genome AF: 0.00796 AC: 1212 AN: 152310 Hom.: 17 Cov.: 32 AF XY: 0.00926 AC XY: 690 AN XY: 74492

African (AFR) AF: 0.00192 AC: 80 AN: 41574

American (AMR) AF: 0.000850 AC: 13 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.0406 AC: 431 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00959 AC: 652 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00872 Hom.: 25

Bravo AF: 0.00521

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00990 AC: 85

ExAC AF: 0.00890 AC: 1080

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00960

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Hereditary intrinsic factor deficiency (3)
-	-	2	not provided (2)
-	-	1	CBLIF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.78	T
PhyloP100		4.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Vest4		0.77
MVP		0.50
MPC		0.62
ClinPred		0.024	T
GERP RS		6.1
gMVP		0.64
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs150884181; hg19: chr11-59610581; COSMIC: COSV57239576; COSMIC: COSV57239576;