17-63632869-G-T

Position:

• chr17-63632869-G-T

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.126+67G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,597,856 control chromosomes in the GnomAD database, including 657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (256 hom., cov: 31)
  • Exomes 𝑓: 0.016 (401 hom.)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.802

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=-0.74).
• BP6: Variant 17-63632869-G-T is Benign according to our data. Variant chr17-63632869-G-T is described in ClinVar as [Benign]. Clinvar id is 1221866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K3	NM_002401.5	c.126+67G>T		intron_variant		ENST00000361733.8	NP_002392.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K3	ENST00000361733.8	c.126+67G>T		intron_variant		1	NM_002401.5	ENSP00000354485	A1

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 6112 AN: 152108 Hom.: 257 Cov.: 31

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0436

GnomAD4 exome AF: 0.0162 AC: 23460 AN: 1445630 Hom.: 401 AF XY: 0.0164 AC XY: 11797 AN XY: 719048

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0208

Gnomad4 ASJ exome AF: 0.0219

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0257

Gnomad4 FIN exome AF: 0.00322

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0220

GnomAD4 genome AF: 0.0402 AC: 6113 AN: 152226 Hom.: 256 Cov.: 31 AF XY: 0.0388 AC XY: 2889 AN XY: 74436

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0390

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0280

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0432

Alfa AF: 0.00595 Hom.: 1

Bravo AF: 0.0458

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	clinical testing	GeneDx	Jun 20, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.59

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: rs58142675; hg19: chr17-61710229;