rs148344770

Positions:

• chr17-45286809-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2 PP2 BP4_Strong BP6_Very_Strong

The NM_003954.5(MAP3K14):​c.774C>G​(p.Phe258Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,613,360 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: MAP3K14 NM_003954.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.31

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 Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAP3K14. . Trascript score misZ 4.5031 (greater than threshold 3.09). GenCC has associacion of gene with NIK deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0067031085).
• BP6: Variant 17-45286809-G-C is Benign according to our data. Variant chr17-45286809-G-C is described in ClinVar as [Benign]. Clinvar id is 544331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K14	NM_003954.5	c.774C>G	p.Phe258Leu	missense_variant	5/16	ENST00000344686.8	NP_003945.2
MAP3K14	XM_047436997.1	c.774C>G	p.Phe258Leu	missense_variant	5/15		XP_047292953.1
MAP3K14	XM_047436998.1	c.774C>G	p.Phe258Leu	missense_variant	6/16		XP_047292954.1
MAP3K14	XM_011525441.3	c.774C>G	p.Phe258Leu	missense_variant	6/17		XP_011523743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K14	ENST00000344686.8	c.774C>G	p.Phe258Leu	missense_variant	5/16	1	NM_003954.5	ENSP00000478552.1
MAP3K14	ENST00000376926.8	c.774C>G	p.Phe258Leu	missense_variant	4/15	1		ENSP00000482657.1
MAP3K14	ENST00000617331.3	c.774C>G	p.Phe258Leu	missense_variant	6/17	5		ENSP00000480974.3

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.000804 AC: 198 AN: 246240 Hom.: 1 AF XY: 0.000523 AC XY: 70 AN XY: 133828

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000641

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: 0.0000988

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000381 AC: 557 AN: 1461044 Hom.: 1 Cov.: 32 AF XY: 0.000332 AC XY: 241 AN XY: 726744

Gnomad4 AFR exome AF: 0.0118

Gnomad4 AMR exome AF: 0.000717

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.00330 AC: 503 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74482

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000960 Hom.: 1

Bravo AF: 0.00389

ESP6500AA AF: 0.0111 AC: 43

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000976 AC: 118

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

NIK deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.60	.;T;.
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Uncertain	0.59	T
REVEL	Benign	0.063
Sift4G	Benign	0.11	.;T;T
Polyphen		0.0010	B;B;B
Vest4		0.30, 0.30
MutPred		0.21		Gain of glycosylation at P254 (P = 0.0893);Gain of glycosylation at P254 (P = 0.0893);Gain of glycosylation at P254 (P = 0.0893);
MVP		0.16
ClinPred		0.035	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.24
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148344770; hg19: chr17-43364176;