chr17-63645770-AACAGCATGTC-A

Position:

• chr17-63645770-AACAGCATGTC-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002401.5(MAP3K3):​c.127-256_127-247del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,016 control chromosomes in the GnomAD database, including 4,301 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.23 (4301 hom., cov: 25)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.194

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 -10 ACMG points.

• BP6: Variant 17-63645770-AACAGCATGTC-A is Benign according to our data. Variant chr17-63645770-AACAGCATGTC-A is described in ClinVar as [Benign]. Clinvar id is 1253109.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K3	NM_002401.5	c.127-256_127-247del		intron_variant		ENST00000361733.8	NP_002392.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K3	ENST00000361733.8	c.127-256_127-247del		intron_variant		1	NM_002401.5	ENSP00000354485	A1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35524 AN: 151896 Hom.: 4298 Cov.: 25

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.247

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.234 AC: 35526 AN: 152016 Hom.: 4301 Cov.: 25 AF XY: 0.228 AC XY: 16968 AN XY: 74322

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.0555

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.244

Alfa AF: 0.256 Hom.: 608

Bravo AF: 0.231

Asia WGS AF: 0.126 AC: 440 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs58194636; hg19: chr17-61723130;