rs12969413

Variant names:

• chr18-58724079-A-G
• rs12969413
• NM_006785.4:c.1222+828A>G

Variant summary

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

The NM_006785.4(MALT1):​c.1222+828A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 152,084 control chromosomes in the GnomAD database, including 14,446 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (14446 hom., cov: 32)
• Consequence: MALT1 NM_006785.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.182
• Publications: 5 publications found

Genes affected

MALT1 (HGNC:6819): (MALT1 paracaspase) This gene encodes a caspase-like protease that plays a role in BCL10-induced activation of NF-kappaB. The protein is a component of the CARMA1-BCL10-MALT1 (CBM) signalosome that triggers NF-kappaB signaling and lymphoctye activation following antigen-receptor stimulation. Mutations in this gene result in immunodeficiency 12 (IMD12). This gene has been found to be recurrently rearranged in chromosomal translocations with other genes in mucosa-associated lymphoid tissue lymphomas, including a t(11;18)(q21;q21) translocation with the baculoviral IAP repeat-containing protein 3 (also known as apoptosis inhibitor 2) locus [BIRC3(API2)-MALT1], and a t(14;18)(q32;q21) translocation with the immunoglobulin heavy chain locus (IGH-MALT1). Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2018]

MALT1 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to MALT1 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

ENSG00000267476 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALT1	NM_006785.4	c.1222+828A>G		intron_variant	Intron 10 of 16	ENST00000649217.2	NP_006776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALT1	ENST00000649217.2	c.1222+828A>G		intron_variant	Intron 10 of 16		NM_006785.4	ENSP00000497997.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60392 AN: 151966 Hom.: 14437 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.432

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.397 AC: 60410 AN: 152084 Hom.: 14446 Cov.: 32 AF XY: 0.399 AC XY: 29628 AN XY: 74316

African (AFR) AF: 0.115 AC: 4790 AN: 41528

American (AMR) AF: 0.414 AC: 6315 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1668 AN: 3472

East Asian (EAS) AF: 0.520 AC: 2685 AN: 5168

South Asian (SAS) AF: 0.513 AC: 2469 AN: 4812

European-Finnish (FIN) AF: 0.506 AC: 5328 AN: 10532

Middle Eastern (MID) AF: 0.462 AC: 135 AN: 292

European-Non Finnish (NFE) AF: 0.523 AC: 35545 AN: 67994

Other (OTH) AF: 0.434 AC: 913 AN: 2106

Alfa AF: 0.394 Hom.: 2423

Bravo AF: 0.373

Asia WGS AF: 0.480 AC: 1667 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs12969413; hg19: chr18-56391311;