chr18-58671684-C-T

Variant names:

• chr18-58671684-C-T
• rs941975162
• NM_006785.4:c.41C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006785.4(MALT1):​c.41C>T​(p.Ser14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S14W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: MALT1 NM_006785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.543
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047681212).

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.41C>T	p.Ser14Leu	missense	Exon 1 of 17	NP_006776.1	Q9UDY8-1
	MALT1	NM_173844.3		c.41C>T	p.Ser14Leu	missense	Exon 1 of 16	NP_776216.1	Q9UDY8-2
	MALT1-AS1	NR_164150.1		n.190G>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.41C>T	p.Ser14Leu	missense	Exon 1 of 17	ENSP00000497997.1	Q9UDY8-1
	MALT1	ENST00000345724.7	TSL:1	c.41C>T	p.Ser14Leu	missense	Exon 1 of 16	ENSP00000304161.3	Q9UDY8-2
	MALT1	ENST00000968608.1		c.41C>T	p.Ser14Leu	missense	Exon 1 of 18	ENSP00000638667.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097438 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 524882

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22600

American (AMR) AF: 0.00 AC: 0 AN: 9002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14260

East Asian (EAS) AF: 0.00 AC: 0 AN: 25766

South Asian (SAS) AF: 0.00 AC: 0 AN: 26706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2900

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 930772

Other (OTH) AF: 0.00 AC: 0 AN: 43514

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.8
DANN	Benign	0.92
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00072	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.54
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.017
Sift	Benign	0.45	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.25		Loss of glycosylation at S14 (P = 0.0032)
MVP		0.12
MPC		0.44
ClinPred		0.039	T
GERP RS		0.25
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.034
gMVP		0.47
Mutation Taster		=92/8	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: rs941975162; hg19: chr18-56338916;