18-58671652-G-T

Variant names:

• chr18-58671652-G-T
• rs373689542
• NM_006785.4:c.9G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006785.4(MALT1):​c.9G>T​(p.Leu3Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,218,716 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (29 hom.)
• Consequence: MALT1 NM_006785.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0310
• 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-AS1 (HGNC:55306): (MALT1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 18-58671652-G-T is Benign according to our data. Variant chr18-58671652-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1160393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.031 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00153 (232/151974) while in subpopulation SAS AF = 0.0456 (220/4828). AF 95% confidence interval is 0.0406. There are 7 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.9G>T	p.Leu3Leu	synonymous	Exon 1 of 17	NP_006776.1	Q9UDY8-1
	MALT1	NM_173844.3		c.9G>T	p.Leu3Leu	synonymous	Exon 1 of 16	NP_776216.1	Q9UDY8-2
	MALT1-AS1	NR_164150.1		n.222C>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALT1	ENST00000649217.2	MANE Select	c.9G>T	p.Leu3Leu	synonymous	Exon 1 of 17	ENSP00000497997.1	Q9UDY8-1
	MALT1	ENST00000345724.7	TSL:1	c.9G>T	p.Leu3Leu	synonymous	Exon 1 of 16	ENSP00000304161.3	Q9UDY8-2
	MALT1	ENST00000968608.1		c.9G>T	p.Leu3Leu	synonymous	Exon 1 of 18	ENSP00000638667.1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 151866 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0457

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00725 AC: 1 AN: 138 AF XY: 0.0106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00113 AC: 1208 AN: 1066742 Hom.: 29 Cov.: 31 AF XY: 0.00133 AC XY: 673 AN XY: 504422

African (AFR) AF: 0.000135 AC: 3 AN: 22222

American (AMR) AF: 0.000257 AC: 2 AN: 7796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13490

East Asian (EAS) AF: 0.000119 AC: 3 AN: 25208

South Asian (SAS) AF: 0.0508 AC: 1029 AN: 20240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20920

Middle Eastern (MID) AF: 0.000708 AC: 2 AN: 2826

European-Non Finnish (NFE) AF: 0.0000658 AC: 60 AN: 911664

Other (OTH) AF: 0.00257 AC: 109 AN: 42376

GnomAD4 genome AF: 0.00153 AC: 232 AN: 151974 Hom.: 7 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74298

African (AFR) AF: 0.000169 AC: 7 AN: 41522

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.0456 AC: 220 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67938

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000283

Asia WGS AF: 0.0210 AC: 73 AN: 3432

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.60
PhyloP100		0.031
PromoterAI		-0.018	Neutral
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: rs373689542; hg19: chr18-56338884;