Genetic Variant NM_002401.5:c.381+66C>A (chr17-63657973-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002401.5(MAP3K3):c.381+66C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000136 in 735,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MAP3K3
NM_002401.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.802

Publications

0 publications found

Variant links:

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]

MAP3K3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002401.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAP3K3	NM_002401.5	MANE Select	c.381+66C>A	intron	N/A	NP_002392.2
MAP3K3	NM_203351.3		c.474+66C>A	intron	N/A	NP_976226.1	Q99759-2
MAP3K3	NM_001363768.2		c.474+66C>A	intron	N/A	NP_001350697.1	J3QRB6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAP3K3	ENST00000361733.8	TSL:1 MANE Select	c.381+66C>A	intron	N/A	ENSP00000354485.4	Q99759-1
MAP3K3	ENST00000361357.7	TSL:1	c.474+66C>A	intron	N/A	ENSP00000354927.3	Q99759-2
MAP3K3	ENST00000579585.5	TSL:1	c.474+66C>A	intron	N/A	ENSP00000461988.1	Q99759-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000136

AC:

AN:

735772

Hom.:

AF XY:

0.00

AC XY:

AN XY:

385042

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

18184

American (AMR)

AF:

0.00

AC:

AN:

32824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18274

East Asian (EAS)

AF:

0.00

AC:

AN:

33574

South Asian (SAS)

AF:

0.00

AC:

AN:

59606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4160

European-Non Finnish (NFE)

AF:

0.00000205

AC:

AN:

488918

Other (OTH)

AF:

0.00

AC:

AN:

34778

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.4

(source)

DANN

Benign

0.57

PhyloP100

0.80

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over