rs2054163065

Variant names:

• chr18-58671692-C-T
• rs2054163065
• NM_006785.4:c.49C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_006785.4(MALT1):​c.49C>T​(p.Pro17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000319 in 1,254,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: MALT1 NM_006785.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.465
• 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: 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 (MetaRNN=0.031184673).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000132 (2/151986) while in subpopulation SAS AF = 0.000414 (2/4830). AF 95% confidence interval is 0.0000729. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.49C>T	p.Pro17Ser	missense	Exon 1 of 17	NP_006776.1	Q9UDY8-1
	MALT1	NM_173844.3		c.49C>T	p.Pro17Ser	missense	Exon 1 of 16	NP_776216.1	Q9UDY8-2
	MALT1-AS1	NR_164150.1		n.182G>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.49C>T	p.Pro17Ser	missense	Exon 1 of 17	ENSP00000497997.1	Q9UDY8-1
	MALT1	ENST00000345724.7	TSL:1	c.49C>T	p.Pro17Ser	missense	Exon 1 of 16	ENSP00000304161.3	Q9UDY8-2
	MALT1	ENST00000968608.1		c.49C>T	p.Pro17Ser	missense	Exon 1 of 18	ENSP00000638667.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151878 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000181 AC: 2 AN: 1102822 Hom.: 0 Cov.: 31 AF XY: 0.00000189 AC XY: 1 AN XY: 528208

African (AFR) AF: 0.00 AC: 0 AN: 22706

American (AMR) AF: 0.00 AC: 0 AN: 9440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14578

East Asian (EAS) AF: 0.00 AC: 0 AN: 25846

South Asian (SAS) AF: 0.0000359 AC: 1 AN: 27892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2946

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 933456

Other (OTH) AF: 0.00 AC: 0 AN: 43764

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151986 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10482

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Combined immunodeficiency due to MALT1 deficiency (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.71	N
PhyloP100		-0.47
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.022
Sift	Benign	0.75	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.051
MutPred		0.15		Gain of phosphorylation at P17 (P = 0.0252)
MVP		0.17
MPC		1.1
ClinPred		0.065	T
GERP RS		1.6
PromoterAI		0.0083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.021
gMVP		0.56
Mutation Taster		=97/3	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: rs2054163065; hg19: chr18-56338924;