16-74674992-G-T

Variant names:

• chr16-74674992-G-T
• rs2144442235
• NM_152649.4:c.1349C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152649.4(MLKL):​c.1349C>A​(p.Ala450Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,296 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A450V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MLKL NM_152649.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.91
• Publications: 0 publications found

Genes affected

MLKL (HGNC:26617): (mixed lineage kinase domain like pseudokinase) This gene belongs to the protein kinase superfamily. The encoded protein contains a protein kinase-like domain; however, is thought to be inactive because it lacks several residues required for activity. This protein plays a critical role in tumor necrosis factor (TNF)-induced necroptosis, a programmed cell death process, via interaction with receptor-interacting protein 3 (RIP3), which is a key signaling molecule in necroptosis pathway. Inhibitor studies and knockdown of this gene inhibited TNF-induced necrosis. High levels of this protein and RIP3 are associated with inflammatory bowel disease in children. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152649.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLKL	NM_152649.4	MANE Select	c.1349C>A	p.Ala450Asp	missense	Exon 10 of 11	NP_689862.1	Q8NB16-1
	MLKL	NM_001142497.3		c.725C>A	p.Ala242Asp	missense	Exon 5 of 6	NP_001135969.1	Q8NB16-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLKL	ENST00000308807.12	TSL:2 MANE Select	c.1349C>A	p.Ala450Asp	missense	Exon 10 of 11	ENSP00000308351.7	Q8NB16-1
	MLKL	ENST00000306247.11	TSL:1	c.725C>A	p.Ala242Asp	missense	Exon 5 of 6	ENSP00000303118.7	Q8NB16-2
	MLKL	ENST00000862152.1		c.1349C>A	p.Ala450Asp	missense	Exon 10 of 12	ENSP00000532211.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.46		Loss of methylation at R449 (P = 0.1473)
MVP		0.83
MPC		0.057
ClinPred		0.72	D
GERP RS		4.8
Varity_R		0.45
gMVP		0.45

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: rs2144442235; hg19: chr16-74708890;