rs7775356

chr6-136635502-T-Achr6-136635502-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005923.4(MAP3K5):c.2016+1823A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 151,880 control chromosomes in the GnomAD database, including 31,888 homozygotes. 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: 𝑓 0.65 (31888 hom., cov: 31)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21

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-AS1 (HGNC:40358): (MAP3K5 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K5	NM_005923.4	c.2016+1823A>T		intron_variant		ENST00000359015.5
MAP3K5-AS1	NR_125858.1	n.164-1429T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K5	ENST00000359015.5	c.2016+1823A>T		intron_variant		1	NM_005923.4	P1
MAP3K5-AS1	ENST00000432477.2	n.212-1429T>A		intron_variant, non_coding_transcript_variant		2
MAP3K5	ENST00000698928.1	c.2343+1823A>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.646 AC: 97968 AN: 151762 Hom.: 31870 Cov.: 31

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.660

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

GnomAD4 genome AF: 0.645 AC: 98036 AN: 151880 Hom.: 31888 Cov.: 31 AF XY: 0.643 AC XY: 47718 AN XY: 74196

Gnomad4 AFR AF: 0.686

Gnomad4 AMR AF: 0.659

Gnomad4 ASJ AF: 0.649

Gnomad4 EAS AF: 0.711

Gnomad4 SAS AF: 0.714

Gnomad4 FIN AF: 0.542

Gnomad4 NFE AF: 0.622

Gnomad4 OTH AF: 0.655

Alfa AF: 0.629 Hom.: 3705

Bravo AF: 0.653

Asia WGS AF: 0.708 AC: 2459 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.28
Dann	Benign	0.35

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: rs7775356; hg19: chr6-136956640;