10-30439079-G-A

Position:

• chr10-30439079-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005204.4(MAP3K8):​c.141G>A​(p.Met47Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,872 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MAP3K8 NM_005204.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99

Genes affected

MAP3K8 (HGNC:6860): (mitogen-activated protein kinase kinase kinase 8) This gene is an oncogene that encodes a member of the serine/threonine protein kinase family. The encoded protein localizes to the cytoplasm and can activate both the MAP kinase and JNK kinase pathways. This protein was shown to activate IkappaB kinases, and thus induce the nuclear production of NF-kappaB. This protein was also found to promote the production of TNF-alpha and IL-2 during T lymphocyte activation. This gene may also utilize a downstream in-frame translation start codon, and thus produce an isoform containing a shorter N-terminus. The shorter isoform has been shown to display weaker transforming activity. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04606083).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K8	NM_005204.4	c.141G>A	p.Met47Ile	missense_variant	3/9	ENST00000263056.6	NP_005195.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K8	ENST00000263056.6	c.141G>A	p.Met47Ile	missense_variant	3/9	1	NM_005204.4	ENSP00000263056	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000636 AC: 16 AN: 251478 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2021

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with MAP3K8-related conditions. This variant is present in population databases (rs745882056, ExAC 0.05%). This sequence change replaces methionine with isoleucine at codon 47 of the MAP3K8 protein (p.Met47Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.49
DEOGEN2	Benign	0.19	T;T;.;.;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.79	.;T;T;T;T;.
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.046	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.;.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.10	N;N;N;N;N;N
REVEL	Benign	0.081
Sift	Benign	0.99	T;T;T;T;T;T
Sift4G	Benign	0.98	T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;B
Vest4		0.11
MutPred		0.31		Loss of disorder (P = 0.0494);Loss of disorder (P = 0.0494);Loss of disorder (P = 0.0494);Loss of disorder (P = 0.0494);Loss of disorder (P = 0.0494);Loss of disorder (P = 0.0494);
MVP		0.38
MPC		0.36
ClinPred		0.028	T
GERP RS		4.7
Varity_R		0.16
gMVP		0.23

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

Other links and lift over

dbSNP: rs745882056; hg19: chr10-30728008;