Variant 16-74691297-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_152649.4(MLKL):c.702A>G(p.Lys234=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,598,684 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 31)

Exomes 𝑓: 0.00080 ( 21 hom. )

Consequence

MLKL
NM_152649.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -4.02

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 made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 16-74691297-T-C is Benign according to our data. Variant chr16-74691297-T-C is described in ClinVar as [Benign]. Clinvar id is 716578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.02 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00227 (337/148494) while in subpopulation AMR AF= 0.0186 (278/14908). AF 95% confidence interval is 0.0168. There are 3 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLKL	NM_152649.4 linkuse as main transcript	c.702A>G	p.Lys234=	synonymous_variant	4/11	ENST00000308807.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLKL	ENST00000308807.12 linkuse as main transcript	c.702A>G	p.Lys234=	synonymous_variant	4/11	2	NM_152649.4	P1	Q8NB16-1
MLKL	ENST00000306247.11 linkuse as main transcript	c.535+1045A>G		intron_variant		1			Q8NB16-2
MLKL	ENST00000571303.1 linkuse as main transcript	c.174A>G	p.Lys58=	synonymous_variant, NMD_transcript_variant	1/6	3

Frequencies

GnomAD3 genomes

AF:

0.00228

AC:

338

AN:

148378

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000696

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00241

Gnomad SAS

AF:

0.000214

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000165

Gnomad OTH

AF:

0.00343

GnomAD3 exomes

AF:

0.00333

AC:

812

AN:

243870

Hom.:

AF XY:

0.00263

AC XY:

347

AN XY:

132126

show subpopulations

Gnomad AFR exome

AF:

0.000569

Gnomad AMR exome

AF:

0.0221

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00291

Gnomad SAS exome

AF:

0.000135

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000540

Gnomad OTH exome

AF:

0.00357

GnomAD4 exome

AF:

0.000796

AC:

1154

AN:

1450190

Hom.:

Cov.:

AF XY:

0.000687

AC XY:

496

AN XY:

721496

show subpopulations

Gnomad4 AFR exome

AF:

0.000398

Gnomad4 AMR exome

AF:

0.0220

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00216

Gnomad4 SAS exome

AF:

0.000153

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000289

Gnomad4 OTH exome

AF:

0.00115

GnomAD4 genome

AF:

0.00227

AC:

337

AN:

148494

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

184

AN XY:

72336

show subpopulations

Gnomad4 AFR

AF:

0.000694

Gnomad4 AMR

AF:

0.0186

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00242

Gnomad4 SAS

AF:

0.000214

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000165

Gnomad4 OTH

AF:

0.00339

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.00350

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.090

DANN

Benign

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over