rs184263319

chr17-45287170-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003954.5(MAP3K14):c.521G>A(p.Cys174Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000645 in 1,613,668 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (8 hom.)
• Consequence: MAP3K14 NM_003954.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.78

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MAP3K14
• BP4: Computational evidence support a benign effect (MetaRNN=0.008482009).
• BP6: Variant 17-45287170-C-T is Benign according to our data. Variant chr17-45287170-C-T is described in ClinVar as [Benign]. Clinvar id is 544327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45287170-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000582 (850/1461360) while in subpopulation AMR AF= 0.0181 (806/44652). AF 95% confidence interval is 0.017. There are 8 homozygotes in gnomad4_exome. There are 359 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K14	NM_003954.5	c.521G>A	p.Cys174Tyr	missense_variant	4/16	ENST00000344686.8
MAP3K14	XM_047436997.1	c.521G>A	p.Cys174Tyr	missense_variant	4/15
MAP3K14	XM_047436998.1	c.521G>A	p.Cys174Tyr	missense_variant	5/16
MAP3K14	XM_011525441.3	c.521G>A	p.Cys174Tyr	missense_variant	5/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K14	ENST00000344686.8	c.521G>A	p.Cys174Tyr	missense_variant	4/16	1	NM_003954.5	P1
MAP3K14	ENST00000376926.8	c.521G>A	p.Cys174Tyr	missense_variant	3/15	1		P1
MAP3K14	ENST00000617331.3	c.521G>A	p.Cys174Tyr	missense_variant	5/17	5		P1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152190 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00275 AC: 682 AN: 248000 Hom.: 9 AF XY: 0.00201 AC XY: 270 AN XY: 134610

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.0192

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: 0.00000890

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.000582 AC: 850 AN: 1461360 Hom.: 8 Cov.: 32 AF XY: 0.000494 AC XY: 359 AN XY: 726946

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0181

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: 0.00000270

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152308 Hom.: 2 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74480

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.00222

ESP6500AA AF: 0.000753 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00213 AC: 257

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NIK deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

MAP3K14-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0085	T;T;T
MetaSVM	Uncertain	-0.15	T
PrimateAI	Uncertain	0.70	T
Polyphen		0.99	D;D;D
Vest4		0.78
MVP		0.44
ClinPred		0.16	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.24

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: rs184263319; hg19: chr17-43364536;