Genetic Variant MLKL:c.1039-1066A>G (chr16-74676830-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0130

Publications

7 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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.1039-1066A>G		intron	N/A	NP_689862.1	Q8NB16-1
	MLKL	NM_001142497.3		c.536-1426A>G		intron	N/A	NP_001135969.1	Q8NB16-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLKL	ENST00000308807.12	TSL:2 MANE Select	c.1039-1066A>G	intron	N/A	ENSP00000308351.7	Q8NB16-1
MLKL	ENST00000306247.11	TSL:1	c.536-1426A>G	intron	N/A	ENSP00000303118.7	Q8NB16-2
MLKL	ENST00000862152.1		c.1039-1066A>G	intron	N/A	ENSP00000532211.1

Frequencies

GnomAD3 genomes

AF:

0.597

AC:

90566

AN:

151824

Hom.:

27162

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AF XY:

1.00

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

1.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.596

AC:

90628

AN:

151942

Hom.:

27181

Cov.:

AF XY:

0.600

AC XY:

44554

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.604

AC:

25028

AN:

41420

American (AMR)

AF:

0.656

AC:

10018

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.499

AC:

1733

AN:

3470

East Asian (EAS)

AF:

0.801

AC:

4134

AN:

5158

South Asian (SAS)

AF:

0.721

AC:

3473

AN:

4820

European-Finnish (FIN)

AF:

0.575

AC:

6061

AN:

10542

Middle Eastern (MID)

AF:

0.568

AC:

167

AN:

294

European-Non Finnish (NFE)

AF:

0.563

AC:

38226

AN:

67954

Other (OTH)

AF:

0.608

AC:

1284

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1894

3787

5681

7574

9468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

756

1512

2268

3024

3780

<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:

0.576

Hom.:

40566

Bravo

AF:

0.600

Asia WGS

AF:

0.745

AC:

2587

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.013

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over