rs149988025

chr18-58709405-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

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. 15/21 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0450

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 474599.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MALT1	NM_006785.4	c.677A>G	p.Lys226Arg	missense_variant	5/17	ENST00000649217.2
LOC105372146	XR_935537.3	n.62-12138T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALT1	ENST00000649217.2	c.677A>G	p.Lys226Arg	missense_variant	5/17		NM_006785.4	P3
	ENST00000588835.1	n.57-12138T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152176 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000764 AC: 184 AN: 240832 Hom.: 0 AF XY: 0.000691 AC XY: 90 AN XY: 130188

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 SAS exome AF: 0.0000357

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.: 0 Cov.: 31 AF XY: 0.000825 AC XY: 592 AN XY: 717872

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.000167

Gnomad4 ASJ exome AF: 0.00355

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.000565

Gnomad4 NFE exome AF: 0.000855

Gnomad4 OTH exome AF: 0.000503

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74462

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00114 Hom.: 1

Bravo AF: 0.000638

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000733 AC: 89

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined immunodeficiency due to MALT1 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	2.3
Dann	Benign	0.96
DEOGEN2	Benign	0.21	T;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.062	N
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0064	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.72	N;N;N
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.34	T
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	T
GERP RS		-0.93
Varity_R		0.095
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs149988025; hg19: chr18-56376637; COSMIC: COSV61934327;