chr16-74675080-G-T

Variant names:

• chr16-74675080-G-T
• rs148386905
• NM_152649.4:c.1261C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152649.4(MLKL):​c.1261C>A​(p.Arg421Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R421H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MLKL NM_152649.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11308947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLKL	NM_152649.4	c.1261C>A	p.Arg421Ser	missense_variant	Exon 10 of 11	ENST00000308807.12	NP_689862.1
MLKL	NM_001142497.3	c.637C>A	p.Arg213Ser	missense_variant	Exon 5 of 6		NP_001135969.1
MLKL	XM_005255834.5	c.1261C>A	p.Arg421Ser	missense_variant	Exon 11 of 12		XP_005255891.1
MLKL	XM_047433704.1	c.*14C>A		3_prime_UTR_variant	Exon 10 of 10		XP_047289660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLKL	ENST00000308807.12	c.1261C>A	p.Arg421Ser	missense_variant	Exon 10 of 11	2	NM_152649.4	ENSP00000308351.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251016 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	0.0093	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.032
DANN	Benign	0.44
DEOGEN2	Benign	0.13	.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.36	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.0	.;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.20
Sift	Benign	0.38	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.011	B;B
Vest4		0.25
MutPred		0.60		.;Loss of ubiquitination at K419 (P = 0.07);
MVP		0.45
MPC		0.021
ClinPred		0.042	T
GERP RS		-8.1
Varity_R		0.30
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148386905; hg19: chr16-74708978;