17-45289226-C-T

Variant names:

• chr17-45289226-C-T
• rs372339711
• NM_003954.5:c.326+10G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003954.5(MAP3K14):​c.326+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,466 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (11 hom.)
• Consequence: MAP3K14 NM_003954.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.695
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-45289226-C-T is Benign according to our data. Variant chr17-45289226-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 544330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003954.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K14	NM_003954.5	MANE Select	c.326+10G>A		intron	N/A	NP_003945.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K14	ENST00000344686.8	TSL:1 MANE Select	c.326+10G>A		intron	N/A	ENSP00000478552.1
	MAP3K14	ENST00000376926.8	TSL:1	c.326+10G>A		intron	N/A	ENSP00000482657.1
	MAP3K14	ENST00000970424.1		c.326+10G>A		intron	N/A	ENSP00000640483.1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00206 AC: 512 AN: 249142 AF XY: 0.00257

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00162 AC: 2361 AN: 1461266 Hom.: 11 Cov.: 30 AF XY: 0.00187 AC XY: 1357 AN XY: 726954

African (AFR) AF: 0.000209 AC: 7 AN: 33476

American (AMR) AF: 0.00154 AC: 69 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00808 AC: 697 AN: 86252

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53392

Middle Eastern (MID) AF: 0.00729 AC: 42 AN: 5762

European-Non Finnish (NFE) AF: 0.00124 AC: 1381 AN: 1111494

Other (OTH) AF: 0.00222 AC: 134 AN: 60366

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152200 Hom.: 1 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74406

African (AFR) AF: 0.000193 AC: 8 AN: 41540

American (AMR) AF: 0.00262 AC: 40 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68000

Other (OTH) AF: 0.00333 AC: 7 AN: 2104

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00134

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	NIK deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.68
PhyloP100		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs372339711; hg19: chr17-43366592;