16-74675071-C-A

Variant names:

• chr16-74675071-C-A
• rs775105387
• NM_152649.4:c.1270G>T

Variant summary

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

The NM_152649.4(MLKL):​c.1270G>T​(p.Val424Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 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. V424M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MLKL NM_152649.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.43
• 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.1270G>T	p.Val424Leu	missense	Exon 10 of 11	NP_689862.1	Q8NB16-1
	MLKL	NM_001142497.3		c.646G>T	p.Val216Leu	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.1270G>T	p.Val424Leu	missense	Exon 10 of 11	ENSP00000308351.7	Q8NB16-1
	MLKL	ENST00000306247.11	TSL:1	c.646G>T	p.Val216Leu	missense	Exon 5 of 6	ENSP00000303118.7	Q8NB16-2
	MLKL	ENST00000862152.1		c.1270G>T	p.Val424Leu	missense	Exon 10 of 12	ENSP00000532211.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Benign	0.030	D
Sift4G	Benign	0.28	T
Polyphen		0.97	D
Vest4		0.35
MutPred		0.60		Loss of methylation at K419 (P = 0.0823)
MVP		0.68
MPC		0.11
ClinPred		0.85	D
GERP RS		4.8
Varity_R		0.53
gMVP		0.62

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: rs775105387; hg19: chr16-74708969;