Variant 4-150583174-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_006439.5(MAB21L2):c.145G>A(p.Glu49Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MAB21L2
NM_006439.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.97

Variant links:

Genes affected

MAB21L2 (HGNC:6758): (mab-21 like 2) This gene is similar to the C. elegans MAB-21 cell fate-determining gene, a downstream target of transforming growth factor-beta signaling. It is thought that this gene may be involved in neural development. The protein encoded by this gene is primarily nuclear, although some cytoplasmic localization has been observed. [provided by RefSeq, Jul 2008]

MAB21L2 links:

LRBA (HGNC:1742): (LPS responsive beige-like anchor protein) The protein encoded by this gene is a member of the WDL-BEACH-WD (WBW) gene family. Its expression is induced in B cells and macrophages by bacterial lipopolysaccharides (LPS). The encoded protein associates with protein kinase A and may be involved in leading intracellular vesicles to activated receptor complexes, which aids in the secretion and/or membrane deposition of immune effector molecules. Defects in this gene are associated with the disorder common variable immunodeficiency-8 with autoimmunity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

LRBA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAB21L2. . Gene score misZ 2.9561 (greater than the threshold 3.09). Trascript score misZ 3.117 (greater than threshold 3.09). GenCC has associacion of gene with colobomatous microphthalmia-rhizomelic dysplasia syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 4-150583174-G-A is Pathogenic according to our data. Variant chr4-150583174-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 139622.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAB21L2	NM_006439.5 linkuse as main transcript	c.145G>A	p.Glu49Lys	missense_variant	1/1	ENST00000317605.6	NP_006430.1
LRBA	NM_001364905.1 linkuse as main transcript	c.6330+4874C>T		intron_variant		ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAB21L2	ENST00000317605.6 linkuse as main transcript	c.145G>A	p.Glu49Lys	missense_variant	1/1		NM_006439.5	ENSP00000324701	P1
LRBA	ENST00000651943.2 linkuse as main transcript	c.6330+4874C>T		intron_variant			NM_001364905.1	ENSP00000498582	P3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Colobomatous microphthalmia-rhizomelic dysplasia syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jun 05, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 05, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.99

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.2

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.93

Gain of ubiquitination at E49 (P = 0.0177);

MVP

0.37

MPC

2.5

ClinPred

0.99

GERP RS

6.2

Varity_R

0.88

gMVP

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over