4-150583351-C-G

Variant names:

• chr4-150583351-C-G
• NM_006439.5:c.322C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006439.5(MAB21L2):​c.322C>G​(p.Arg108Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAB21L2 NM_006439.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.769

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAB21L2	NM_006439.5	c.322C>G	p.Arg108Gly	missense_variant	Exon 1 of 1	ENST00000317605.6	NP_006430.1
LRBA	NM_001364905.1	c.6330+4697G>C		intron_variant	Intron 40 of 56	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAB21L2	ENST00000317605.6	c.322C>G	p.Arg108Gly	missense_variant	Exon 1 of 1	6	NM_006439.5	ENSP00000324701.4
LRBA	ENST00000651943.2	c.6330+4697G>C		intron_variant	Intron 40 of 56		NM_001364905.1	ENSP00000498582.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 21, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.50
Sift	Benign	0.23	T
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.83		Gain of glycosylation at S109 (P = 0.0135);
MVP		0.50
MPC		2.6
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.57
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-151504503;