rs35533328

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_006785.4(MALT1):ā€‹c.1921A>Gā€‹(p.Ile641Val) variant causes a missense change. The variant allele was found at a frequency of 0.000309 in 1,612,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0017 ( 0 hom., cov: 32)
Exomes š‘“: 0.00016 ( 0 hom. )

Consequence

MALT1
NM_006785.4 missense

Scores

1
17

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.88
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0038812459).
BP6
Variant 18-58745675-A-G is Benign according to our data. Variant chr18-58745675-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 474595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00173 (263/152182) while in subpopulation AFR AF= 0.00621 (258/41524). AF 95% confidence interval is 0.00559. There are 0 homozygotes in gnomad4. There are 125 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MALT1NM_006785.4 linkuse as main transcriptc.1921A>G p.Ile641Val missense_variant 16/17 ENST00000649217.2 NP_006776.1 Q9UDY8-1A8K5S1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MALT1ENST00000649217.2 linkuse as main transcriptc.1921A>G p.Ile641Val missense_variant 16/17 NM_006785.4 ENSP00000497997.1 Q9UDY8-1

Frequencies

GnomAD3 genomes
AF:
0.00172
AC:
261
AN:
152066
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00618
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000428
AC:
107
AN:
250266
Hom.:
0
AF XY:
0.000281
AC XY:
38
AN XY:
135266
show subpopulations
Gnomad AFR exome
AF:
0.00585
Gnomad AMR exome
AF:
0.000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000329
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000162
AC:
236
AN:
1460260
Hom.:
0
Cov.:
31
AF XY:
0.000127
AC XY:
92
AN XY:
726460
show subpopulations
Gnomad4 AFR exome
AF:
0.00587
Gnomad4 AMR exome
AF:
0.000382
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000465
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000298
GnomAD4 genome
AF:
0.00173
AC:
263
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.00168
AC XY:
125
AN XY:
74394
show subpopulations
Gnomad4 AFR
AF:
0.00621
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000603
Hom.:
0
Bravo
AF:
0.00200
ESP6500AA
AF:
0.00431
AC:
19
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000593
AC:
72
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Combined immunodeficiency due to MALT1 deficiency Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 11, 2023- -
not provided Benign:1
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.64
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
17
DANN
Benign
0.56
DEOGEN2
Benign
0.21
T;T;.
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.37
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.82
.;T;T
MetaRNN
Benign
0.0039
T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-1.1
N;N;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
0.17
N;.;N
REVEL
Benign
0.11
Sift
Benign
1.0
T;.;T
Sift4G
Benign
1.0
T;.;T
Polyphen
0.0
B;B;B
Vest4
0.10
MVP
0.25
MPC
0.41
ClinPred
0.017
T
GERP RS
3.2
Varity_R
0.10
gMVP
0.13

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35533328; hg19: chr18-56412907; API