rs200919386

Variant names:

• chr18-58700600-C-T
• rs200919386
• NM_006785.4:c.649+9C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. 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
• Publications: 2 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 -9 ACMG points.

• 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 VariationId is 474596.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.649+9C>T		intron	N/A	NP_006776.1
	MALT1	NM_173844.3		c.649+9C>T		intron	N/A	NP_776216.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALT1	ENST00000649217.2	MANE Select	c.649+9C>T		intron	N/A	ENSP00000497997.1
	MALT1	ENST00000345724.7	TSL:1	c.649+9C>T		intron	N/A	ENSP00000304161.3
	MALT1	ENST00000968608.1		c.772+9C>T		intron	N/A	ENSP00000638667.1

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

GnomAD2 exomes AF: 0.000812 AC: 175 AN: 215450 AF XY: 0.000888

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 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

African (AFR) AF: 0.000128 AC: 4 AN: 31178

American (AMR) AF: 0.00135 AC: 47 AN: 34784

Ashkenazi Jewish (ASJ) AF: 0.000163 AC: 4 AN: 24508

East Asian (EAS) AF: 0.00 AC: 0 AN: 38552

South Asian (SAS) AF: 0.0000507 AC: 4 AN: 78854

European-Finnish (FIN) AF: 0.0000569 AC: 3 AN: 52724

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5634

European-Non Finnish (NFE) AF: 0.00115 AC: 1271 AN: 1100458

Other (OTH) AF: 0.000766 AC: 45 AN: 58772

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

African (AFR) AF: 0.000169 AC: 7 AN: 41518

American (AMR) AF: 0.00183 AC: 28 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.000865

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Combined immunodeficiency due to MALT1 deficiency (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		-0.016
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200919386; hg19: chr18-56367832;