18-58671710-G-C

Variant names:

• chr18-58671710-G-C
• rs994799429
• NM_006785.4:c.67G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006785.4(MALT1):​c.67G>C​(p.Ala23Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A23T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MALT1 NM_006785.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.981

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050418377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALT1	NM_006785.4	c.67G>C	p.Ala23Pro	missense_variant	Exon 1 of 17	ENST00000649217.2	NP_006776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALT1	ENST00000649217.2	c.67G>C	p.Ala23Pro	missense_variant	Exon 1 of 17		NM_006785.4	ENSP00000497997.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1120236 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 538912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.4
DANN	Benign	0.55
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00091	N
LIST_S2	Benign	0.40	.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.92	N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.030	N;.;N
REVEL	Benign	0.0090
Sift	Benign	0.40	T;.;T
Sift4G	Benign	0.30	T;.;T
Polyphen		0.0	B;B;B
Vest4		0.073
MutPred		0.31		Gain of catalytic residue at A23 (P = 0.0067);Gain of catalytic residue at A23 (P = 0.0067);Gain of catalytic residue at A23 (P = 0.0067);
MVP		0.15
MPC		0.64
ClinPred		0.092	T
GERP RS		-1.9
Varity_R		0.061
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs994799429; hg19: chr18-56338942;