rs11867907

Positions:

• chr17-45267712-G-A

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.2020C>T​(p.His674Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,610 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (10 hom.)
• Consequence: MAP3K14 NM_003954.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.982

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:):

ACMG classification

Verdict is Benign. Variant got -19 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=0.0031523705).
• BP6: Variant 17-45267712-G-A is Benign according to our data. Variant chr17-45267712-G-A is described in ClinVar as [Benign]. Clinvar id is 544333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00659 (1004/152348) while in subpopulation AFR AF= 0.0219 (909/41576). AF 95% confidence interval is 0.0207. There are 8 homozygotes in gnomad4. There are 472 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K14	NM_003954.5	c.2020C>T	p.His674Tyr	missense_variant	12/16	ENST00000344686.8	NP_003945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K14	ENST00000344686.8	c.2020C>T	p.His674Tyr	missense_variant	12/16	1	NM_003954.5	ENSP00000478552.1

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1003 AN: 152230 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

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: 0.000103

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00164 AC: 404 AN: 246674 Hom.: 2 AF XY: 0.00133 AC XY: 178 AN XY: 134092

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000722

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000604 AC: 882 AN: 1461262 Hom.: 10 Cov.: 31 AF XY: 0.000498 AC XY: 362 AN XY: 726940

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00659 AC: 1004 AN: 152348 Hom.: 8 Cov.: 32 AF XY: 0.00634 AC XY: 472 AN XY: 74498

Gnomad4 AFR AF: 0.0219

Gnomad4 AMR AF: 0.00522

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00268 Hom.: 0

Bravo AF: 0.00785

ESP6500AA AF: 0.0200 AC: 78

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00201 AC: 243

Asia WGS AF: 0.00115 AC: 4 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 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	13
DANN	Benign	0.40
DEOGEN2	Benign	0.23	T;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.42	.;T;.
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N
PrimateAI	Benign	0.24	T
REVEL	Benign	0.18
Sift4G	Benign	1.0	.;T;T
Polyphen		0.0	B;B;B
Vest4		0.18
MVP		0.37
ClinPred		0.017	T
GERP RS		4.0
Varity_R		0.19
gMVP		0.15

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: rs11867907; hg19: chr17-43345079;