NM_006439.5:c.1A>C

Variant names:

• chr4-150583030-A-C
• rs1771601609
• NM_006439.5:c.1A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006439.5(MAB21L2):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAB21L2 NM_006439.5 initiator_codon
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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]

LRBA Gene-Disease associations (from GenCC):

• combined immunodeficiency due to LRBA deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 83 codons. Genomic position: 150583276. Lost 0.229 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-150583030-A-C is Pathogenic according to our data. Variant chr4-150583030-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 929565.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006439.5. 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
	MAB21L2	NM_006439.5	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 1	NP_006430.1	Q9Y586
	LRBA	NM_001364905.1	MANE Select	c.6330+5018T>G		intron	N/A	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.6363+5018T>G		intron	N/A	NP_001427359.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAB21L2	ENST00000317605.6	TSL:6 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 1	ENSP00000324701.4	Q9Y586
	LRBA	ENST00000651943.2	MANE Select	c.6330+5018T>G		intron	N/A	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.6363+5018T>G		intron	N/A	ENSP00000349629.3	P50851-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1435016 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 710600

African (AFR) AF: 0.00 AC: 0 AN: 32752

American (AMR) AF: 0.00 AC: 0 AN: 42188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24264

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.00 AC: 0 AN: 82442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097116

Other (OTH) AF: 0.00 AC: 0 AN: 58986

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Colobomatous microphthalmia-rhizomelic dysplasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-1.1	T
PhyloP100		9.3
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.018	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.094	B
Vest4		0.78
MutPred		0.72		Loss of MoRF binding (P = 0.0718)
MVP		0.57
ClinPred		0.97	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.54
gMVP		0.82
Mutation Taster		=16/184	disease causing (ClinVar)

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: rs1771601609; hg19: chr4-151504182;