16-74675380-G-A

Variant names:

• chr16-74675380-G-A
• rs370078597
• ENST00000306247.11:c.560C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001142497.3(MLKL):​c.560C>T​(p.Ser187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: MLKL NM_001142497.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.408

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011514813).
• BP6: Variant 16-74675380-G-A is Benign according to our data. Variant chr16-74675380-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3203547.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLKL	NM_152649.4	c.1215C>T	p.Ile405Ile	synonymous_variant	Exon 9 of 11	ENST00000308807.12	NP_689862.1
MLKL	NM_001142497.3	c.560C>T	p.Ser187Leu	missense_variant	Exon 4 of 6		NP_001135969.1
MLKL	XM_005255834.5	c.1215C>T	p.Ile405Ile	synonymous_variant	Exon 10 of 12		XP_005255891.1
MLKL	XM_047433704.1	c.1215C>T	p.Ile405Ile	synonymous_variant	Exon 9 of 10		XP_047289660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLKL	ENST00000308807.12	c.1215C>T	p.Ile405Ile	synonymous_variant	Exon 9 of 11	2	NM_152649.4	ENSP00000308351.7

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 251336 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135846

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000171 AC: 250 AN: 1461768 Hom.: 0 Cov.: 32 AF XY: 0.000179 AC XY: 130 AN XY: 727204

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74448

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000177 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 28, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.96
DANN	Benign	0.64
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.93	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.013
Sift	Benign	0.65	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.10
ClinPred		0.0029	T
GERP RS		-2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs370078597; hg19: chr16-74709278;