rs74847855

Positions:

• chr18-58700591-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006785.4(MALT1):​c.649A>G​(p.Arg217Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,587,716 control chromosomes in the GnomAD database, including 1,300 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (101 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1199 hom.)
• Consequence: MALT1 NM_006785.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004342
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.806

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017837882).
• BP6: Variant 18-58700591-A-G is Benign according to our data. Variant chr18-58700591-A-G is described in ClinVar as [Benign]. Clinvar id is 474597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MALT1	NM_006785.4	c.649A>G	p.Arg217Gly	missense_variant, splice_region_variant	4/17	ENST00000649217.2	NP_006776.1
LOC105372146	XR_935537.3	n.62-3324T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MALT1	ENST00000649217.2	c.649A>G	p.Arg217Gly	missense_variant, splice_region_variant	4/17		NM_006785.4	ENSP00000497997	P3
	ENST00000588835.1	n.57-3324T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4322 AN: 152216 Hom.: 101 Cov.: 32

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0626

Gnomad FIN AF: 0.0346

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0398

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0371 AC: 8313 AN: 224104 Hom.: 189 AF XY: 0.0394 AC XY: 4780 AN XY: 121326

Gnomad AFR exome AF: 0.00578

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0752

Gnomad EAS exome AF: 0.000731

Gnomad SAS exome AF: 0.0654

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0360

GnomAD4 exome AF: 0.0378 AC: 54226 AN: 1435382 Hom.: 1199 Cov.: 30 AF XY: 0.0390 AC XY: 27825 AN XY: 713410

Gnomad4 AFR exome AF: 0.00476

Gnomad4 AMR exome AF: 0.0250

Gnomad4 ASJ exome AF: 0.0705

Gnomad4 EAS exome AF: 0.000669

Gnomad4 SAS exome AF: 0.0640

Gnomad4 FIN exome AF: 0.0352

Gnomad4 NFE exome AF: 0.0382

Gnomad4 OTH exome AF: 0.0341

GnomAD4 genome AF: 0.0283 AC: 4314 AN: 152334 Hom.: 101 Cov.: 32 AF XY: 0.0285 AC XY: 2126 AN XY: 74498

Gnomad4 AFR AF: 0.00597

Gnomad4 AMR AF: 0.0252

Gnomad4 ASJ AF: 0.0597

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0620

Gnomad4 FIN AF: 0.0346

Gnomad4 NFE AF: 0.0398

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0373 Hom.: 221

Bravo AF: 0.0251

TwinsUK AF: 0.0399 AC: 148

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.0405 AC: 348

ExAC AF: 0.0370 AC: 4495

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to MALT1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.8
DANN	Benign	0.76
DEOGEN2	Benign	0.20	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.65	.;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.74	N;N;N
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.66	N;.;N
REVEL	Benign	0.038
Sift	Benign	0.45	T;.;T
Sift4G	Benign	0.42	T;.;T
Polyphen		0.0	B;B;B
Vest4		0.12
MPC		0.64
ClinPred		0.0011	T
GERP RS		-0.31
Varity_R		0.10
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.030
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: rs74847855; hg19: chr18-56367823; COSMIC: COSV61936263; COSMIC: COSV61936263;