rs11595876

Variant names:

• chr10-52767002-T-C
• rs11595876
• NM_001378373.1:c.*1135A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378373.1(MBL2):​c.*1135A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0461 in 152,020 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (226 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: MBL2 NM_001378373.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.853
• Publications: 10 publications found

Genes affected

MBL2 (HGNC:6922): (mannose binding lectin 2) This gene encodes the soluble mannose-binding lectin or mannose-binding protein found in serum. The protein encoded belongs to the collectin family and is an important element in the innate immune system. The protein recognizes and binds to mannose and N-acetylglucosamine on many microorganisms, including bacteria, yeast, and viruses including influenza virus, HIV and SARS-CoV. This binding activates the classical complement pathway. Deficiencies of this gene have been associated with susceptibility to autoimmune and infectious diseases. [provided by RefSeq, Jun 2020]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBL2	NM_001378373.1	c.*1135A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000674931.1	NP_001365302.1
MBL2	NM_000242.3	c.*1135A>G		3_prime_UTR_variant	Exon 4 of 4		NP_000233.1
MBL2	NM_001378374.1	c.*1135A>G		3_prime_UTR_variant	Exon 5 of 5		NP_001365303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBL2	ENST00000674931.1	c.*1135A>G		3_prime_UTR_variant	Exon 5 of 5		NM_001378373.1	ENSP00000502789.1
MBL2	ENST00000373968.3	c.*1135A>G		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000363079.3
MBL2	ENST00000675947.1	c.*1135A>G		3_prime_UTR_variant	Exon 5 of 5			ENSP00000502615.1

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7019 AN: 151902 Hom.: 225 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0417

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0462

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0684

Gnomad OTH AF: 0.0445

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0461 AC: 7015 AN: 152020 Hom.: 226 Cov.: 32 AF XY: 0.0442 AC XY: 3285 AN XY: 74340

African (AFR) AF: 0.0152 AC: 630 AN: 41404

American (AMR) AF: 0.0415 AC: 634 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 348 AN: 3456

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5166

South Asian (SAS) AF: 0.0189 AC: 91 AN: 4820

European-Finnish (FIN) AF: 0.0462 AC: 490 AN: 10602

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0684 AC: 4650 AN: 67990

Other (OTH) AF: 0.0435 AC: 92 AN: 2114

Alfa AF: 0.0607 Hom.: 507

Bravo AF: 0.0447

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mannose-binding lectin deficiency Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.25
DANN	Benign	0.45
PhyloP100		-0.85
Mutation Taster		=100/0	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: rs11595876; hg19: chr10-54526762;