ENST00000306247.11:c.578G>T

Variant names:

• chr16-74675362-C-A
• rs141519819
• ENST00000306247.11:c.578G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000306247.11(MLKL):​c.578G>T​(p.Arg193Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/15 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. R193H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLKL ENST00000306247.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.704

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09272894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLKL	NM_152649.4	c.1233G>T	p.Pro411Pro	synonymous_variant	Exon 9 of 11	ENST00000308807.12	NP_689862.1
MLKL	NM_001142497.3	c.578G>T	p.Arg193Leu	missense_variant	Exon 4 of 6		NP_001135969.1
MLKL	XM_005255834.5	c.1233G>T	p.Pro411Pro	synonymous_variant	Exon 10 of 12		XP_005255891.1
MLKL	XM_047433704.1	c.1233G>T	p.Pro411Pro	synonymous_variant	Exon 9 of 10		XP_047289660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLKL	ENST00000308807.12	c.1233G>T	p.Pro411Pro	synonymous_variant	Exon 9 of 11	2	NM_152649.4	ENSP00000308351.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251438 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.15
DANN	Benign	0.95
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.023
Sift	Benign	0.16	T
Sift4G	Benign	0.26	T
Polyphen		0.0050	B
Vest4		0.22
MutPred		0.39		Loss of MoRF binding (P = 0.0021);
MVP		0.076
ClinPred		0.089	T
GERP RS		-9.9

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: rs141519819; hg19: chr16-74709260;