18-58700591-A-G

Variant names:

• chr18-58700591-A-G
• rs74847855
• NM_006785.4:c.649A>G

Variant summary

Our verdict is Benign. The variant received -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. 17/23 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
• Publications: 15 publications found

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

ENSG00000267476 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006785.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALT1	NM_006785.4	MANE Select	c.649A>G	p.Arg217Gly	missense splice_region	Exon 4 of 17	NP_006776.1
	MALT1	NM_173844.3		c.649A>G	p.Arg217Gly	missense splice_region	Exon 4 of 16	NP_776216.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALT1	ENST00000649217.2	MANE Select	c.649A>G	p.Arg217Gly	missense splice_region	Exon 4 of 17	ENSP00000497997.1
	MALT1	ENST00000345724.7	TSL:1	c.649A>G	p.Arg217Gly	missense splice_region	Exon 4 of 16	ENSP00000304161.3
	MALT1	ENST00000648670.1		n.439A>G		splice_region non_coding_transcript_exon	Exon 3 of 16	ENSP00000497173.1

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

GnomAD2 exomes AF: 0.0371 AC: 8313 AN: 224104 AF XY: 0.0394

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 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

African (AFR) AF: 0.00476 AC: 151 AN: 31746

American (AMR) AF: 0.0250 AC: 927 AN: 37030

Ashkenazi Jewish (ASJ) AF: 0.0705 AC: 1762 AN: 24978

East Asian (EAS) AF: 0.000669 AC: 26 AN: 38890

South Asian (SAS) AF: 0.0640 AC: 5141 AN: 80372

European-Finnish (FIN) AF: 0.0352 AC: 1864 AN: 52992

Middle Eastern (MID) AF: 0.0282 AC: 160 AN: 5674

European-Non Finnish (NFE) AF: 0.0382 AC: 42176 AN: 1104428

Other (OTH) AF: 0.0341 AC: 2019 AN: 59272

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

African (AFR) AF: 0.00597 AC: 248 AN: 41572

American (AMR) AF: 0.0252 AC: 386 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 207 AN: 3468

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0620 AC: 299 AN: 4824

European-Finnish (FIN) AF: 0.0346 AC: 368 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0398 AC: 2708 AN: 68030

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.0362 Hom.: 428

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.74	N
PhyloP100		0.81
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.66	N
REVEL	Benign	0.038
Sift	Benign	0.45	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.12
MPC		0.64
ClinPred		0.0011	T
GERP RS		-0.31
Varity_R		0.10
gMVP		0.38
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74847855; hg19: chr18-56367823; COSMIC: COSV61936263; COSMIC: COSV61936263;