chr16-74695364-A-G

Position:

• chr16-74695364-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_152649.4(MLKL):​c.394T>C​(p.Ser132Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,614,154 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., cov: 32)
  • Exomes 𝑓: 0.016 (234 hom.)
• Consequence: MLKL NM_152649.4 missense
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 0.0560

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050573945).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1814/152272) while in subpopulation NFE AF= 0.0181 (1232/68022). AF 95% confidence interval is 0.0173. There are 13 homozygotes in gnomad4. There are 892 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLKL	NM_152649.4	c.394T>C	p.Ser132Pro	missense_variant	2/11	ENST00000308807.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLKL	ENST00000308807.12	c.394T>C	p.Ser132Pro	missense_variant	2/11	2	NM_152649.4	P1
MLKL	ENST00000306247.11	c.394T>C	p.Ser132Pro	missense_variant	2/6	1
MLKL	ENST00000573267.1	c.394T>C	p.Ser132Pro	missense_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1814 AN: 152154 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00810

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0140 AC: 3526 AN: 251488 Hom.: 54 AF XY: 0.0148 AC XY: 2005 AN XY: 135918

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00671

Gnomad ASJ exome AF: 0.0311

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0145

Gnomad FIN exome AF: 0.00776

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0159 AC: 23243 AN: 1461882 Hom.: 234 Cov.: 32 AF XY: 0.0159 AC XY: 11543 AN XY: 727244

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.00727

Gnomad4 ASJ exome AF: 0.0306

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.00833

Gnomad4 NFE exome AF: 0.0175

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0119 AC: 1814 AN: 152272 Hom.: 13 Cov.: 32 AF XY: 0.0120 AC XY: 892 AN XY: 74458

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00810

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0184 Hom.: 36

Bravo AF: 0.0116

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0144 AC: 124

ExAC AF: 0.0143 AC: 1739

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0197

EpiControl AF: 0.0190

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Chronic multifocal osteomyelitis Other:1

association, no assertion criteria provided

research

Vinuesa Lab, Australian National University

Jan 01, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	.;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.49	T;T;T
MetaRNN	Benign	0.0051	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.90	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Benign	0.093
Sift	Benign	0.13	T;T;.
Sift4G	Pathogenic	0.0	D;T;.
Polyphen		0.99	D;D;.
Vest4		0.16
MPC		0.020
ClinPred		0.012	T
GERP RS		-2.0
Varity_R		0.52
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35589326; hg19: chr16-74729262; COSMIC: COSV99077031; COSMIC: COSV99077031;