rs34389205

Variant names:

• chr16-74675712-G-A
• rs34389205
• NM_152649.4:c.1091C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-74675712-G-A
• chr16-74675712-G-C
• chr16-74675712-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_152649.4(MLKL):​c.1091C>T​(p.Thr364Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,614,006 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.016 (40 hom., cov: 32)
  • Exomes 𝑓: 0.019 (362 hom.)
• Consequence: MLKL NM_152649.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027821064).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0161 (2454/152206) while in subpopulation NFE AF = 0.0224 (1526/68016). AF 95% confidence interval is 0.0215. There are 40 homozygotes in GnomAd4. There are 1322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLKL	NM_152649.4	MANE Select	c.1091C>T	p.Thr364Met	missense	Exon 8 of 11	NP_689862.1
	MLKL	NM_001142497.3		c.536-308C>T		intron	N/A	NP_001135969.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLKL	ENST00000308807.12	TSL:2 MANE Select	c.1091C>T	p.Thr364Met	missense	Exon 8 of 11	ENSP00000308351.7
	MLKL	ENST00000306247.11	TSL:1	c.536-308C>T		intron	N/A	ENSP00000303118.7
	MLKL	ENST00000570846.1	TSL:2	n.2702C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2454 AN: 152088 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00937

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0167 AC: 4210 AN: 251382 AF XY: 0.0166

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0481

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0195 AC: 28433 AN: 1461800 Hom.: 362 Cov.: 32 AF XY: 0.0191 AC XY: 13916 AN XY: 727204

African (AFR) AF: 0.00311 AC: 104 AN: 33480

American (AMR) AF: 0.00651 AC: 291 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 309 AN: 26132

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39694

South Asian (SAS) AF: 0.00679 AC: 586 AN: 86254

European-Finnish (FIN) AF: 0.0477 AC: 2549 AN: 53396

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.0212 AC: 23561 AN: 1111962

Other (OTH) AF: 0.0165 AC: 995 AN: 60394

GnomAD4 genome AF: 0.0161 AC: 2454 AN: 152206 Hom.: 40 Cov.: 32 AF XY: 0.0178 AC XY: 1322 AN XY: 74402

African (AFR) AF: 0.00296 AC: 123 AN: 41544

American (AMR) AF: 0.00936 AC: 143 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4824

European-Finnish (FIN) AF: 0.0538 AC: 569 AN: 10584

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0224 AC: 1526 AN: 68016

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.0180 Hom.: 80

Bravo AF: 0.0122

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00523 AC: 23

ESP6500EA AF: 0.0216 AC: 186

ExAC AF: 0.0169 AC: 2050

EpiCase AF: 0.0211

EpiControl AF: 0.0200

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.4
DANN	Benign	0.87
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.027
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Benign	0.066	T
Polyphen		0.013	B
Vest4		0.049
MPC		0.020
ClinPred		0.00063	T
GERP RS		-0.42
Varity_R		0.027
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34389205; hg19: chr16-74709610; COSMIC: COSV58206803;