rs149988025

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_006785.4(MALT1):c.677A>G(p.Lys226Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000779 in 1,596,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K226K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

MALT1
NM_006785.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0450

Publications

6 publications found

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]

MALT1 Gene-Disease associations (from GenCC):

combined immunodeficiency due to MALT1 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

MALT1 links:

ENSG00000267476 (HGNC:):

ENSG00000267476 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064280927).

BP6

Variant 18-58709405-A-G is Benign according to our data. Variant chr18-58709405-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 474599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000919 (140/152294) while in subpopulation NFE AF = 0.00156 (106/68032). AF 95% confidence interval is 0.00132. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALT1	NM_006785.4 link	c.677A>G	p.Lys226Arg	missense_variant	Exon 5 of 17	ENST00000649217.2	NP_006776.1	Q9UDY8-1A8K5S1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALT1	ENST00000649217.2 link	c.677A>G	p.Lys226Arg	missense_variant	Exon 5 of 17		NM_006785.4	ENSP00000497997.1		Q9UDY8-1

Frequencies

GnomAD3 genomes

AF:

0.000920

AC:

140

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000764

AC:

184

AN:

240832

AF XY:

0.000691

show subpopulations

Gnomad AFR exome

AF:

0.000317

Gnomad AMR exome

AF:

0.000189

Gnomad ASJ exome

AF:

0.00317

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000419

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000764

AC:

1104

AN:

1444530

Hom.:

Cov.:

AF XY:

0.000825

AC XY:

592

AN XY:

717872

show subpopulations

African (AFR)

AF:

0.0000305

AC:

AN:

32762

American (AMR)

AF:

0.000167

AC:

AN:

41986

Ashkenazi Jewish (ASJ)

AF:

0.00355

AC:

AN:

25616

East Asian (EAS)

AF:

0.00

AC:

AN:

39142

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82262

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

53076

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.000855

AC:

944

AN:

1104370

Other (OTH)

AF:

0.000503

AC:

AN:

59604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000919

AC:

140

AN:

152294

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41562

American (AMR)

AF:

0.000327

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00156

AC:

106

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.000638

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000733

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MALT1: BP4 -

Combined immunodeficiency due to MALT1 deficiency

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.3

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.21

T;T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.71

.;T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.0064

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.72

N;N;N

PhyloP100

0.045

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.37

N;.;N

REVEL

Benign

0.033

Sift

Benign

0.59

T;.;T

Sift4G

Benign

0.69

T;.;T

Polyphen

0.0

B;B;B

Vest4

0.094

MVP

0.23

MPC

0.41

ClinPred

0.0049

GERP RS

-0.93

Varity_R

0.095

gMVP

0.44

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over