rs558928879

Variant names:

• chr18-58733376-TCTTA-T
• rs558928879
• NM_006785.4:c.1223-20_1223-17delCTTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006785.4(MALT1):​c.1223-20_1223-17delCTTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00794 in 1,533,728 control chromosomes in the GnomAD database, including 63 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0082 (58 hom.)
• Consequence: MALT1 NM_006785.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.09
• 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000267476 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 18-58733376-TCTTA-T is Benign according to our data. Variant chr18-58733376-TCTTA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00534 (813/152324) while in subpopulation NFE AF = 0.00919 (625/68006). AF 95% confidence interval is 0.00859. There are 5 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALT1	NM_006785.4	MANE Select	c.1223-20_1223-17delCTTA		intron	N/A	NP_006776.1	Q9UDY8-1
	MALT1	NM_173844.3		c.1190-20_1190-17delCTTA		intron	N/A	NP_776216.1	Q9UDY8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALT1	ENST00000649217.2	MANE Select	c.1223-20_1223-17delCTTA		intron	N/A	ENSP00000497997.1	Q9UDY8-1
	MALT1	ENST00000345724.7	TSL:1	c.1190-20_1190-17delCTTA		intron	N/A	ENSP00000304161.3	Q9UDY8-2
	MALT1	ENST00000968608.1		c.1346-20_1346-17delCTTA		intron	N/A	ENSP00000638667.1

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 814 AN: 152206 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00560 AC: 1265 AN: 226088 AF XY: 0.00588

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00563

Gnomad NFE exome AF: 0.00894

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00823 AC: 11366 AN: 1381404 Hom.: 58 AF XY: 0.00796 AC XY: 5497 AN XY: 690228

African (AFR) AF: 0.00118 AC: 36 AN: 30608

American (AMR) AF: 0.00200 AC: 73 AN: 36510

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 30 AN: 24264

East Asian (EAS) AF: 0.00 AC: 0 AN: 39300

South Asian (SAS) AF: 0.00290 AC: 230 AN: 79422

European-Finnish (FIN) AF: 0.00557 AC: 294 AN: 52756

Middle Eastern (MID) AF: 0.00364 AC: 20 AN: 5502

European-Non Finnish (NFE) AF: 0.00977 AC: 10316 AN: 1055692

Other (OTH) AF: 0.00640 AC: 367 AN: 57350

GnomAD4 genome AF: 0.00534 AC: 813 AN: 152324 Hom.: 5 Cov.: 33 AF XY: 0.00495 AC XY: 369 AN XY: 74492

African (AFR) AF: 0.00144 AC: 60 AN: 41572

American (AMR) AF: 0.00170 AC: 26 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00919 AC: 625 AN: 68006

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00560 Hom.: 0

Bravo AF: 0.00527

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Combined immunodeficiency due to MALT1 deficiency (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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: rs558928879; hg19: chr18-56400608;