rs17685379

Variant names:

• chr17-45274682-C-T
• rs17685379
• NM_003954.5:c.1291-89G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003954.5(MAP3K14):​c.1291-89G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,476,580 control chromosomes in the GnomAD database, including 10,998 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.099 (931 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10067 hom.)
• Consequence: MAP3K14 NM_003954.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.305
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• NIK deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-45274682-C-T is Benign according to our data. Variant chr17-45274682-C-T is described in ClinVar as Benign. ClinVar VariationId is 2628305.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K14	NM_003954.5	c.1291-89G>A		intron_variant	Intron 6 of 15	ENST00000344686.8	NP_003945.2
MAP3K14	XM_047436997.1	c.1291-89G>A		intron_variant	Intron 6 of 14		XP_047292953.1
MAP3K14	XM_047436998.1	c.1291-89G>A		intron_variant	Intron 7 of 15		XP_047292954.1
MAP3K14	XM_011525441.3	c.1291-89G>A		intron_variant	Intron 7 of 16		XP_011523743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K14	ENST00000344686.8	c.1291-89G>A		intron_variant	Intron 6 of 15	1	NM_003954.5	ENSP00000478552.1
MAP3K14	ENST00000376926.8	c.1291-89G>A		intron_variant	Intron 5 of 14	1		ENSP00000482657.1
MAP3K14	ENST00000617331.3	c.1291-89G>A		intron_variant	Intron 7 of 16	5		ENSP00000480974.3
MAP3K14	ENST00000680632.1	n.139-89G>A		intron_variant	Intron 1 of 10			ENSP00000505027.1

Frequencies

GnomAD3 genomes AF: 0.0995 AC: 15126 AN: 152086 Hom.: 930 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.0571

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.0874

Gnomad EAS AF: 0.0943

Gnomad SAS AF: 0.0712

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.121 AC: 159700 AN: 1324374 Hom.: 10067 AF XY: 0.119 AC XY: 77993 AN XY: 653320

African (AFR) AF: 0.0245 AC: 734 AN: 30012

American (AMR) AF: 0.138 AC: 4192 AN: 30464

Ashkenazi Jewish (ASJ) AF: 0.0927 AC: 1920 AN: 20710

East Asian (EAS) AF: 0.104 AC: 3925 AN: 37776

South Asian (SAS) AF: 0.0636 AC: 4508 AN: 70866

European-Finnish (FIN) AF: 0.131 AC: 5244 AN: 40028

Middle Eastern (MID) AF: 0.104 AC: 390 AN: 3756

European-Non Finnish (NFE) AF: 0.128 AC: 132554 AN: 1035514

Other (OTH) AF: 0.113 AC: 6233 AN: 55248

GnomAD4 genome AF: 0.0994 AC: 15134 AN: 152206 Hom.: 931 Cov.: 32 AF XY: 0.0997 AC XY: 7419 AN XY: 74408

African (AFR) AF: 0.0280 AC: 1164 AN: 41548

American (AMR) AF: 0.152 AC: 2325 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0874 AC: 303 AN: 3468

East Asian (EAS) AF: 0.0944 AC: 488 AN: 5172

South Asian (SAS) AF: 0.0709 AC: 342 AN: 4826

European-Finnish (FIN) AF: 0.129 AC: 1370 AN: 10594

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8823 AN: 67992

Other (OTH) AF: 0.109 AC: 230 AN: 2112

Alfa AF: 0.0871 Hom.: 309

Bravo AF: 0.0967

Asia WGS AF: 0.113 AC: 392 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.86
DANN	Benign	0.76
PhyloP100		-0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17685379; hg19: chr17-43352049;