17-45266691-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003954.5(MAP3K14):c.2434-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,604,980 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (6 hom.)
• Consequence: MAP3K14 NM_003954.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.75

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:44359): (MAP3K14 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-45266691-C-T is Benign according to our data. Variant chr17-45266691-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 544336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45266691-C-T is described in Lovd as [Likely_benign].
• 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.2434-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000344686.8
MAP3K14-AS1	NR_110325.1	n.260-422C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K14	ENST00000344686.8	c.2434-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003954.5	P1
MAP3K14-AS1	ENST00000657572.1	n.170-422C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 569 AN: 152090 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00104 AC: 252 AN: 243242 Hom.: 1 AF XY: 0.000945 AC XY: 125 AN XY: 132210

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000796

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000184

Gnomad OTH exome AF: 0.00170

GnomAD4 exome AF: 0.000427 AC: 621 AN: 1452772 Hom.: 6 Cov.: 30 AF XY: 0.000398 AC XY: 287 AN XY: 720910

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.000927

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000754

Gnomad4 NFE exome AF: 0.0000425

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152208 Hom.: 3 Cov.: 32 AF XY: 0.00359 AC XY: 267 AN XY: 74404

Gnomad4 AFR AF: 0.0128

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00174 Hom.: 1

Bravo AF: 0.00429

Asia WGS AF: 0.00433 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -

NIK deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.6
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34836788; hg19: chr17-43344058;