NM_152649.4:c.394T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

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. 14/21 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

Scores

Clinical Significance

association no assertion criteria provided O:1

Conservation

PhyloP100: 0.0560

Publications

17 publications found

Variant links:

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]

MLKL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 13 AR gene

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.394T>C	p.Ser132Pro	missense	Exon 2 of 11	NP_689862.1	Q8NB16-1
	MLKL	NM_001142497.3		c.394T>C	p.Ser132Pro	missense	Exon 2 of 6	NP_001135969.1	Q8NB16-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLKL	ENST00000308807.12	TSL:2 MANE Select	c.394T>C	p.Ser132Pro	missense	Exon 2 of 11	ENSP00000308351.7	Q8NB16-1
MLKL	ENST00000306247.11	TSL:1	c.394T>C	p.Ser132Pro	missense	Exon 2 of 6	ENSP00000303118.7	Q8NB16-2
MLKL	ENST00000862152.1		c.394T>C	p.Ser132Pro	missense	Exon 2 of 12	ENSP00000532211.1

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1814

AN:

152154

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0140

AC:

3526

AN:

251488

AF XY:

0.0148

show subpopulations

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 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.:

AF XY:

0.0159

AC XY:

11543

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

33480

American (AMR)

AF:

0.00727

AC:

325

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0306

AC:

801

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0134

AC:

1159

AN:

86258

European-Finnish (FIN)

AF:

0.00833

AC:

445

AN:

53412

Middle Eastern (MID)

AF:

0.00884

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0175

AC:

19436

AN:

1112008

Other (OTH)

AF:

0.0156

AC:

945

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1503

3006

4508

6011

7514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

692

1384

2076

2768

3460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0119

AC:

1814

AN:

152272

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

892

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00308

AC:

128

AN:

41572

American (AMR)

AF:

0.0103

AC:

157

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0303

AC:

105

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.0137

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00810

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0181

AC:

1232

AN:

68022

Other (OTH)

AF:

0.0166

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

191

286

382

477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0175

Hom.:

Bravo

AF:

0.0116

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0144

AC:

124

ExAC

AF:

0.0143

AC:

1739

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0197

EpiControl

AF:

0.0190

ClinVar

ClinVar submissions

Significance:association

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Chronic multifocal osteomyelitis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.90

PhyloP100

0.056

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.6

REVEL

Benign

0.093

Sift

Benign

0.13

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.16

MPC

0.020

ClinPred

0.012

GERP RS

-2.0

Varity_R

0.52

gMVP

0.19

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over