rs367938510

chr17-45274129-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Strong BP6_Moderate

The NM_003954.5(MAP3K14):c.1546G>A(p.Val516Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,609,690 control chromosomes in the GnomAD database, including 6 homozygotes. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (6 hom.)
• Consequence: MAP3K14 NM_003954.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.47

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MAP3K14
• BP4: Computational evidence support a benign effect (MetaRNN=0.015393168).
• BP6: Variant 17-45274129-C-T is Benign according to our data. Variant chr17-45274129-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 544325.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-45274129-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K14	NM_003954.5	c.1546G>A	p.Val516Ile	missense_variant	8/16	ENST00000344686.8
MAP3K14	XM_047436997.1	c.1546G>A	p.Val516Ile	missense_variant	8/15
MAP3K14	XM_047436998.1	c.1546G>A	p.Val516Ile	missense_variant	9/16
MAP3K14	XM_011525441.3	c.1546G>A	p.Val516Ile	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K14	ENST00000344686.8	c.1546G>A	p.Val516Ile	missense_variant	8/16	1	NM_003954.5	P1
MAP3K14	ENST00000376926.8	c.1546G>A	p.Val516Ile	missense_variant	7/15	1		P1
MAP3K14	ENST00000617331.3	c.1546G>A	p.Val516Ile	missense_variant	9/17	5		P1
MAP3K14	ENST00000680632.1	c.394G>A	p.Val132Ile	missense_variant, NMD_transcript_variant	3/11

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00108 AC: 259 AN: 239846 Hom.: 0 AF XY: 0.00118 AC XY: 153 AN XY: 130120

Gnomad AFR exome AF: 0.000339

Gnomad AMR exome AF: 0.000623

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00260

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.000686

GnomAD4 exome AF: 0.00172 AC: 2508 AN: 1457380 Hom.: 6 Cov.: 32 AF XY: 0.00178 AC XY: 1290 AN XY: 724486

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000792

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00190

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74478

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00148

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00107 Hom.: 1

Bravo AF: 0.00125

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000761 AC: 3

ESP6500EA AF: 0.000844 AC: 7

ExAC AF: 0.00110 AC: 133

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

NIK deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	18
Dann	Benign	0.67
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.77	D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.41	N;N;N
PrimateAI	Benign	0.40	T
Polyphen		0.022	B;B;B
Vest4		0.20, 0.20
MVP		0.27
ClinPred		0.058	T
GERP RS		3.0
Varity_R		0.032
gMVP		0.48

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: rs367938510; hg19: chr17-43351496;