18-58700591-A-C

Variant names:

• chr18-58700591-A-C
• rs74847855
• NM_006785.4:c.649A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_006785.4(MALT1):​c.649A>C​(p.Arg217Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MALT1 NM_006785.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005226
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.806
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP7: Synonymous conserved (PhyloP=0.806 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006785.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALT1	NM_006785.4	MANE Select	c.649A>C	p.Arg217Arg	splice_region synonymous	Exon 4 of 17	NP_006776.1
	MALT1	NM_173844.3		c.649A>C	p.Arg217Arg	splice_region synonymous	Exon 4 of 16	NP_776216.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALT1	ENST00000649217.2	MANE Select	c.649A>C	p.Arg217Arg	splice_region synonymous	Exon 4 of 17	ENSP00000497997.1
	MALT1	ENST00000345724.7	TSL:1	c.649A>C	p.Arg217Arg	splice_region synonymous	Exon 4 of 16	ENSP00000304161.3
	MALT1	ENST00000648670.1		n.439A>C		splice_region non_coding_transcript_exon	Exon 3 of 16	ENSP00000497173.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435582 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 713514

African (AFR) AF: 0.00 AC: 0 AN: 31746

American (AMR) AF: 0.00 AC: 0 AN: 37034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24984

East Asian (EAS) AF: 0.00 AC: 0 AN: 38894

South Asian (SAS) AF: 0.00 AC: 0 AN: 80414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104550

Other (OTH) AF: 0.00 AC: 0 AN: 59284

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.5
DANN	Benign	0.60
PhyloP100		0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000052
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs74847855; hg19: chr18-56367823;