rs747466210

Variant names:

• chr17-45286763-G-A
• rs747466210
• NM_003954.5:c.820C>T

Variant summary

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

The NM_003954.5(MAP3K14):​c.820C>T​(p.Pro274Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAP3K14 NM_003954.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

Genes affected

MAP3K14 (HGNC:6853): (mitogen-activated protein kinase kinase kinase 14) This gene encodes mitogen-activated protein kinase kinase kinase 14, which is a serine/threonine protein-kinase. This kinase binds to TRAF2 and stimulates NF-kappaB activity. It shares sequence similarity with several other MAPKK kinases. It participates in an NF-kappaB-inducing signalling cascade common to receptors of the tumour-necrosis/nerve-growth factor (TNF/NGF) family and to the interleukin-1 type-I receptor. [provided by RefSeq, Jul 2008]

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=0.12510368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K14	NM_003954.5	c.820C>T	p.Pro274Ser	missense_variant	Exon 5 of 16	ENST00000344686.8	NP_003945.2
MAP3K14	XM_047436997.1	c.820C>T	p.Pro274Ser	missense_variant	Exon 5 of 15		XP_047292953.1
MAP3K14	XM_047436998.1	c.820C>T	p.Pro274Ser	missense_variant	Exon 6 of 16		XP_047292954.1
MAP3K14	XM_011525441.3	c.820C>T	p.Pro274Ser	missense_variant	Exon 6 of 17		XP_011523743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K14	ENST00000344686.8	c.820C>T	p.Pro274Ser	missense_variant	Exon 5 of 16	1	NM_003954.5	ENSP00000478552.1
MAP3K14	ENST00000376926.8	c.820C>T	p.Pro274Ser	missense_variant	Exon 4 of 15	1		ENSP00000482657.1
MAP3K14	ENST00000617331.3	c.820C>T	p.Pro274Ser	missense_variant	Exon 6 of 17	5		ENSP00000480974.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245400 Hom.: 0 AF XY: 0.00000751 AC XY: 1 AN XY: 133136

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: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460172 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726178

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

NIK deficiency Uncertain:1

Nov 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with MAP3K14-related disease. This variant is present in population databases (rs747466210, ExAC 0.007%). This sequence change replaces proline with serine at codon 274 of the MAP3K14 protein (p.Pro274Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	.;T;.
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Benign	0.36	T
REVEL	Benign	0.031
Sift4G	Uncertain	0.040	.;D;D
Polyphen		0.44	B;B;B
Vest4		0.32, 0.30
MutPred		0.30		Loss of glycosylation at K276 (P = 0.175);Loss of glycosylation at K276 (P = 0.175);Loss of glycosylation at K276 (P = 0.175);
MVP		0.44
ClinPred		0.58	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
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: rs747466210; hg19: chr17-43364130;