rs56302559

chr17-45267442-T-Cchr17-45267442-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_003954.5(MAP3K14):c.2290A>G(p.Thr764Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,606,984 control chromosomes in the GnomAD database, including 8 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T764I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (6 hom.)
• Consequence: MAP3K14 NM_003954.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.701

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MAP3K14
• BP4: Computational evidence support a benign effect (MetaRNN=0.007188499).
• BP6: Variant 17-45267442-T-C is Benign according to our data. Variant chr17-45267442-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478059.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr17-45267442-T-C 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.2290A>G	p.Thr764Ala	missense_variant	12/16	ENST00000344686.8
MAP3K14-AS1	NR_110325.1	n.475+114T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K14	ENST00000344686.8	c.2290A>G	p.Thr764Ala	missense_variant	12/16	1	NM_003954.5	P1
MAP3K14-AS1	ENST00000657572.1	n.385+114T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152216 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00188 AC: 442 AN: 235416 Hom.: 0 AF XY: 0.00177 AC XY: 227 AN XY: 128208

Gnomad AFR exome AF: 0.000856

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000136

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00356

Gnomad OTH exome AF: 0.00122

GnomAD4 exome AF: 0.00299 AC: 4352 AN: 1454650 Hom.: 6 Cov.: 31 AF XY: 0.00282 AC XY: 2037 AN XY: 723094

Gnomad4 AFR exome AF: 0.000630

Gnomad4 AMR exome AF: 0.000485

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000106

Gnomad4 FIN exome AF: 0.000905

Gnomad4 NFE exome AF: 0.00375

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152334 Hom.: 2 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74510

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00244 Hom.: 0

Bravo AF: 0.00178

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00193 AC: 16

ExAC AF: 0.00167 AC: 202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 13, 2020

The MAP3K14 c.2290A>G; p.Thr764Ala variant (rs56302559), to our knowledge, is not reported in the medical literature but is reported as likely benign in ClinVar (Variation ID: 478059). This variant is found in the general population with an overall allele frequency of 0.19% (495/266794 alleles) in the Genome Aggregation Database. The threonine at codon 764 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr764Ala variant is uncertain at this time. -

NIK deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	15
Dann	Benign	0.85
DEOGEN2	Benign	0.29	T;T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.56	D
MetaRNN	Benign	0.0072	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L;L;L
PrimateAI	Benign	0.35	T
Polyphen		0.058	B;B;B
Vest4		0.12, 0.12
MVP		0.13
ClinPred		0.0071	T
GERP RS		3.7
Varity_R		0.043
gMVP		0.22

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: rs56302559; hg19: chr17-43344809; COSMIC: COSV60924434; COSMIC: COSV60924434;