rs4940736

Variant names:

• chr18-58678199-T-A
• rs4940736
• NM_006785.4:c.210-2971T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006785.4(MALT1):​c.210-2971T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 152,152 control chromosomes in the GnomAD database, including 1,622 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1622 hom., cov: 33)
• Consequence: MALT1 NM_006785.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.515
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MALT1	NM_006785.4	c.210-2971T>A		intron_variant	Intron 1 of 16	ENST00000649217.2	NP_006776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MALT1	ENST00000649217.2	c.210-2971T>A		intron_variant	Intron 1 of 16		NM_006785.4	ENSP00000497997.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17945 AN: 152034 Hom.: 1619 Cov.: 33

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0795

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.0714

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.0877

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.118 AC: 17982 AN: 152152 Hom.: 1622 Cov.: 33 AF XY: 0.119 AC XY: 8841 AN XY: 74392

African (AFR) AF: 0.258 AC: 10711 AN: 41484

American (AMR) AF: 0.0796 AC: 1217 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3470

East Asian (EAS) AF: 0.0714 AC: 370 AN: 5184

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4828

European-Finnish (FIN) AF: 0.122 AC: 1297 AN: 10588

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0591 AC: 4015 AN: 67992

Other (OTH) AF: 0.0892 AC: 188 AN: 2108

Alfa AF: 0.101 Hom.: 129

Bravo AF: 0.123

Asia WGS AF: 0.0770 AC: 267 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.4
DANN	Benign	0.82
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

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: rs4940736; hg19: chr18-56345431;