rs200919386

chr18-58700600-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_006785.4(MALT1):c.649+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000955 in 1,577,662 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (1 hom.)
• Consequence: MALT1 NM_006785.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0160

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-58700600-C-T is Benign according to our data. Variant chr18-58700600-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474596.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr18-58700600-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000841 (128/152198) while in subpopulation AMR AF= 0.00183 (28/15290). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 52 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.649+9C>T		intron_variant		ENST00000649217.2
LOC105372146	XR_935537.3	n.62-3333G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALT1	ENST00000649217.2	c.649+9C>T		intron_variant			NM_006785.4	P3
	ENST00000588835.1	n.57-3333G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000842 AC: 128 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000812 AC: 175 AN: 215450 Hom.: 0 AF XY: 0.000888 AC XY: 104 AN XY: 117082

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.000249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000843

Gnomad FIN exome AF: 0.0000484

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.000967 AC: 1379 AN: 1425464 Hom.: 1 Cov.: 30 AF XY: 0.00101 AC XY: 715 AN XY: 708368

Gnomad4 AFR exome AF: 0.000128

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.000163

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000507

Gnomad4 FIN exome AF: 0.0000569

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.000766

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74416

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.000865

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined immunodeficiency due to MALT1 deficiency Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 29, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	13
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs200919386; hg19: chr18-56367832;