rs11574819

Positions:

• chr17-45287272-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_003954.5(MAP3K14):​c.419G>A​(p.Ser140Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00997 in 1,613,992 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (5 hom., cov: 32)
  • Exomes 𝑓: 0.010 (93 hom.)
• Consequence: MAP3K14 NM_003954.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.24

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 -15 ACMG points.

• 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=0.0069752634).
• BP6: Variant 17-45287272-C-T is Benign according to our data. Variant chr17-45287272-C-T is described in ClinVar as [Benign]. Clinvar id is 544329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45287272-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K14	NM_003954.5	c.419G>A	p.Ser140Asn	missense_variant	4/16	ENST00000344686.8	NP_003945.2
MAP3K14	XM_047436997.1	c.419G>A	p.Ser140Asn	missense_variant	4/15		XP_047292953.1
MAP3K14	XM_047436998.1	c.419G>A	p.Ser140Asn	missense_variant	5/16		XP_047292954.1
MAP3K14	XM_011525441.3	c.419G>A	p.Ser140Asn	missense_variant	5/17		XP_011523743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K14	ENST00000344686.8	c.419G>A	p.Ser140Asn	missense_variant	4/16	1	NM_003954.5	ENSP00000478552.1
MAP3K14	ENST00000376926.8	c.419G>A	p.Ser140Asn	missense_variant	3/15	1		ENSP00000482657.1
MAP3K14	ENST00000617331.3	c.419G>A	p.Ser140Asn	missense_variant	5/17	5		ENSP00000480974.3

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1147 AN: 152178 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00829 AC: 2066 AN: 249242 Hom.: 18 AF XY: 0.00842 AC XY: 1139 AN XY: 135224

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.00797

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00500

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0102 AC: 14940 AN: 1461696 Hom.: 93 Cov.: 32 AF XY: 0.0100 AC XY: 7307 AN XY: 727132

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00774

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00526

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00931

GnomAD4 genome AF: 0.00753 AC: 1147 AN: 152296 Hom.: 5 Cov.: 32 AF XY: 0.00687 AC XY: 512 AN XY: 74474

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.00915

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00838

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.0103 Hom.: 17

Bravo AF: 0.00717

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00222 AC: 9

ESP6500EA AF: 0.0124 AC: 103

ExAC AF: 0.00796 AC: 963

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MAP3K14: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

NIK deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.23	T;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.65	.;T;.
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.36	T
REVEL	Benign	0.046
Sift4G	Benign	0.80	.;T;T
Polyphen		0.0	B;B;B
Vest4		0.15, 0.16
MVP		0.39
ClinPred		0.058	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.052

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: rs11574819; hg19: chr17-43364638;