Genetic Variant MAP3K5:c.96+94_96+103delCGGCGCGGCG (chr6-136792541-CCGCCGCGCCG-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001438058.1(MAP3K5):c.96+94_96+103delCGGCGCGGCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000847 in 165,254 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

MAP3K5
NM_001438058.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.332

Publications

2 publications found

Variant links:

Genes affected

MAP3K5 (HGNC:6857): (mitogen-activated protein kinase kinase kinase 5) Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. MAPKKK5 contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK. [provided by RefSeq, Jul 2008]

MAP3K5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 136 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438058.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MAP3K5	NM_001438058.1		c.96+94_96+103delCGGCGCGGCG	intron	N/A	NP_001424987.1
MAP3K5	NM_005923.4	MANE Select	c.-394_-385delCGGCGCGGCG	upstream_gene	N/A	NP_005914.1
MAP3K5	NM_001438579.1		c.-836_-827delCGGCGCGGCG	upstream_gene	N/A	NP_001425508.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MAP3K5	ENST00000698928.1		c.96+94_96+103delCGGCGCGGCG	intron	N/A	ENSP00000514039.1
MAP3K5	ENST00000359015.5	TSL:1 MANE Select	c.-394_-385delCGGCGCGGCG	upstream_gene	N/A	ENSP00000351908.4
MAP3K5	ENST00000954598.1		c.-394_-385delCGGCGCGGCG	upstream_gene	N/A	ENSP00000624657.1

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

138

AN:

148982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00192

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000663

Gnomad ASJ

AF:

0.00696

Gnomad EAS

AF:

0.000406

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.000101

Gnomad MID

AF:

0.00968

Gnomad NFE

AF:

0.000194

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000247

AC:

AN:

16162

Hom.:

AF XY:

0.000378

AC XY:

AN XY:

7928

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:

266

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000274

AC:

AN:

14608

Other (OTH)

AF:

0.00

AC:

AN:

538

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0618289), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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

AF:

0.000912

AC:

136

AN:

149092

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

72712

show subpopulations

African (AFR)

AF:

0.00189

AC:

AN:

40736

American (AMR)

AF:

0.000662

AC:

AN:

15108

Ashkenazi Jewish (ASJ)

AF:

0.00696

AC:

AN:

3446

East Asian (EAS)

AF:

0.000407

AC:

AN:

4912

South Asian (SAS)

AF:

0.00147

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.000101

AC:

AN:

9928

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000194

AC:

AN:

66932

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

806

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.33

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over