rs770530971

Variant names:

• chr11-59842516-GTTC-G
• rs770530971
• NM_005142.3:c.435_437delGAA

Your query was ambiguous. Multiple possible variants found:

• chr11-59842516-GTTC-G
• chr11-59842516-GTTC-GTTCTTC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_005142.3(CBLIF):​c.435_437delGAA​(p.Lys145del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,614,012 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (3 hom.)
• Consequence: CBLIF NM_005142.3 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.39
• 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: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005142.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 11-59842516-GTTC-G is Benign according to our data. Variant chr11-59842516-GTTC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 208192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0016 (244/152346) while in subpopulation AMR AF = 0.0049 (75/15298). AF 95% confidence interval is 0.00401. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.435_437delGAA	p.Lys145del	disruptive_inframe_deletion	Exon 4 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.435_437delGAA	p.Lys145del	disruptive_inframe_deletion	Exon 4 of 9	ENSP00000257248.2
	CBLIF	ENST00000525058.5	TSL:2	n.*402_*404delGAA		non_coding_transcript_exon	Exon 4 of 9	ENSP00000433196.1
	CBLIF	ENST00000532070.1	TSL:2	n.925_927delGAA		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00128 AC: 321 AN: 251080 AF XY: 0.00127

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00216 AC: 3151 AN: 1461666 Hom.: 3 AF XY: 0.00219 AC XY: 1594 AN XY: 727130

African (AFR) AF: 0.000239 AC: 8 AN: 33474

American (AMR) AF: 0.00143 AC: 64 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

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

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86246

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00265 AC: 2946 AN: 1111982

Other (OTH) AF: 0.00179 AC: 108 AN: 60380

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74502

African (AFR) AF: 0.000337 AC: 14 AN: 41592

American (AMR) AF: 0.00490 AC: 75 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00223 AC: 152 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000312 Hom.: 0

Bravo AF: 0.00145

EpiCase AF: 0.00196

EpiControl AF: 0.00166

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary intrinsic factor deficiency (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=71/29	polymorphism

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: rs770530971; hg19: chr11-59609989;