17-45264701-C-T

Variant names:

• chr17-45264701-C-T
• rs1567984601
• NM_003954.5:c.2779G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003954.5(MAP3K14):​c.2779G>A​(p.Ala927Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAP3K14 NM_003954.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.82
• Publications: 0 publications found

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]

MAP3K14-AS1 (HGNC:44359): (MAP3K14 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003954.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K14	NM_003954.5	MANE Select	c.2779G>A	p.Ala927Thr	missense	Exon 16 of 16	NP_003945.2	Q99558
	MAP3K14-AS1	NR_024434.2		n.80-2412C>T		intron	N/A
	MAP3K14-AS1	NR_024435.2		n.265-1549C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K14	ENST00000344686.8	TSL:1 MANE Select	c.2779G>A	p.Ala927Thr	missense	Exon 16 of 16	ENSP00000478552.1	Q99558
	MAP3K14	ENST00000376926.8	TSL:1	c.2779G>A	p.Ala927Thr	missense	Exon 15 of 15	ENSP00000482657.1	Q99558
	MAP3K14-AS1	ENST00000585351.2	TSL:1	n.154-1549C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	NIK deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.8
PrimateAI	Uncertain	0.63	T
REVEL	Uncertain	0.36
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.36		Gain of phosphorylation at A927 (P = 0.0596)
MVP		0.34
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.33
gMVP		0.79

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: rs1567984601; hg19: chr17-43342068;