chr16-74682652-G-C

Variant names:

• chr16-74682652-G-C
• rs151198441
• NM_152649.4:c.955C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152649.4(MLKL):​c.955C>G​(p.Arg319Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLKL NM_152649.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001270
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLKL	NM_152649.4	c.955C>G	p.Arg319Gly	missense_variant, splice_region_variant	Exon 6 of 11	ENST00000308807.12	NP_689862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLKL	ENST00000308807.12	c.955C>G	p.Arg319Gly	missense_variant, splice_region_variant	Exon 6 of 11	2	NM_152649.4	ENSP00000308351.7
MLKL	ENST00000306247.11	c.536-7248C>G		intron_variant	Intron 3 of 5	1		ENSP00000303118.7
MLKL	ENST00000571303.1	n.424C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 6	3		ENSP00000461110.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250856 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135532

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.069	T
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.016	D
Polyphen		0.98	D
Vest4		0.49
MVP		0.80
MPC		0.097
ClinPred		0.97	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.070		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: rs151198441; hg19: chr16-74716550;