16-74676830-T-C

Position:

• chr16-74676830-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152649.4(MLKL):​c.1039-1066A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 151,944 control chromosomes in the GnomAD database, including 27,182 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.60 (27181 hom., cov: 32)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: MLKL NM_152649.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0130

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLKL	NM_152649.4	c.1039-1066A>G		intron_variant		ENST00000308807.12	NP_689862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLKL	ENST00000308807.12	c.1039-1066A>G		intron_variant		2	NM_152649.4	ENSP00000308351	P1

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90566 AN: 151824 Hom.: 27162 Cov.: 32

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.656

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.610

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 2 AN XY: 2

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.596 AC: 90628 AN: 151942 Hom.: 27181 Cov.: 32 AF XY: 0.600 AC XY: 44554 AN XY: 74272

Gnomad4 AFR AF: 0.604

Gnomad4 AMR AF: 0.656

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.801

Gnomad4 SAS AF: 0.721

Gnomad4 FIN AF: 0.575

Gnomad4 NFE AF: 0.563

Gnomad4 OTH AF: 0.608

Alfa AF: 0.574 Hom.: 25146

Bravo AF: 0.600

Asia WGS AF: 0.745 AC: 2587 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.89

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: rs7196369; hg19: chr16-74710728;