16-74675361-AC-GT

Variant names:

• chr16-74675361-AC-GT
• NM_152649.4:c.1233_1234delGTinsAC

Variant summary

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

The NM_152649.4(MLKL):​c.1233_1234delGTinsAC​(p.Phe412Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P411P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLKL NM_152649.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.49
• 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 0 ACMG points.

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.1233_1234delGTinsAC	p.Phe412Leu	missense	N/A	NP_689862.1	Q8NB16-1
	MLKL	NM_001142497.3		c.578_579delGTinsAC	p.Arg193His	missense	N/A	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.1233_1234delGTinsAC	p.Phe412Leu	missense	N/A	ENSP00000308351.7	Q8NB16-1
	MLKL	ENST00000306247.11	TSL:1	c.578_579delGTinsAC	p.Arg193His	missense	N/A	ENSP00000303118.7	Q8NB16-2
	MLKL	ENST00000862152.1		c.1233_1234delGTinsAC	p.Phe412Leu	missense	N/A	ENSP00000532211.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr16-74709259;