17-63657696-T-C

Position:

• chr17-63657696-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002401.5(MAP3K3):​c.268-98T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 545,268 control chromosomes in the GnomAD database, including 29,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (14307 hom., cov: 32)
  • Exomes 𝑓: 0.26 (15364 hom.)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.01

Genes affected

MAP3K3 (HGNC:6855): (mitogen-activated protein kinase kinase kinase 3) This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse Mekk3. Its catalytic domain is closely related to those of several other kinases, including mouse Mekk2, tobacco NPK, and yeast Ste11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed. This protein directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively; it does not regulate the p38 pathway. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NFKB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-63657696-T-C is Benign according to our data. Variant chr17-63657696-T-C is described in ClinVar as [Benign]. Clinvar id is 1244132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K3	NM_002401.5	c.268-98T>C		intron_variant		ENST00000361733.8	NP_002392.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K3	ENST00000361733.8	c.268-98T>C		intron_variant		1	NM_002401.5	ENSP00000354485	A1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57578 AN: 152010 Hom.: 14254 Cov.: 32

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.348

GnomAD4 exome AF: 0.256 AC: 100730 AN: 393140 Hom.: 15364 AF XY: 0.252 AC XY: 52588 AN XY: 208704

Gnomad4 AFR exome AF: 0.704

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.0493

Gnomad4 SAS exome AF: 0.176

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.275

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.379 AC: 57675 AN: 152128 Hom.: 14307 Cov.: 32 AF XY: 0.369 AC XY: 27479 AN XY: 74378

Gnomad4 AFR AF: 0.711

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.0556

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.344

Alfa AF: 0.299 Hom.: 7654

Bravo AF: 0.398

Asia WGS AF: 0.162 AC: 566 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.069
DANN	Benign	0.36

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: rs6504173; hg19: chr17-61735056;