16-74675071-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLKL	NM_152649.4	c.1270G>T	p.Val424Leu	missense_variant	Exon 10 of 11	ENST00000308807.12	NP_689862.1
MLKL	NM_001142497.3	c.646G>T	p.Val216Leu	missense_variant	Exon 5 of 6		NP_001135969.1
MLKL	XM_005255834.5	c.1270G>T	p.Val424Leu	missense_variant	Exon 11 of 12		XP_005255891.1
MLKL	XM_047433704.1	c.*23G>T		3_prime_UTR_variant	Exon 10 of 10		XP_047289660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLKL	ENST00000308807.12	c.1270G>T	p.Val424Leu	missense_variant	Exon 10 of 11	2	NM_152649.4	ENSP00000308351.7

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.7	.;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.28
Sift	Benign	0.030	D;D
Sift4G	Benign	0.28	T;T
Polyphen		0.97	D;P
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

Publications

LitVar

Other links and lift over

dbSNP: rs775105387; hg19: chr16-74708969;