Variant 6-136583645-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_005923.4(MAP3K5):c.3321C>T(p.Ala1107Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00576 in 1,614,148 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.011 ( 19 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 93 hom. )

Consequence

MAP3K5
NM_005923.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.05

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:

MAP3K5 (HGNC:):

MAP3K5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 6-136583645-G-A is Benign according to our data. Variant chr6-136583645-G-A is described in ClinVar as [Benign]. Clinvar id is 792056.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=2.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0107 (1629/152296) while in subpopulation EAS AF= 0.0394 (204/5178). AF 95% confidence interval is 0.035. There are 19 homozygotes in gnomad4. There are 786 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1629 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K5	NM_005923.4 linkuse as main transcript	c.3321C>T	p.Ala1107Ala	synonymous_variant	24/30	ENST00000359015.5	NP_005914.1	Q99683-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MAP3K5	ENST00000359015.5 linkuse as main transcript	c.3321C>T	p.Ala1107Ala	synonymous_variant	24/30	1	NM_005923.4	ENSP00000351908.4	Q99683-1
MAP3K5	ENST00000698928.1 linkuse as main transcript	c.3648C>T	p.Ala1216Ala	synonymous_variant	25/31			ENSP00000514039.1	A0A8V8TMH5
MAP3K5	ENST00000463140.1 linkuse as main transcript	n.202C>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1611

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0393

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00241

Gnomad OTH

AF:

0.00955

GnomAD3 exomes

AF:

0.00862

AC:

2168

AN:

251388

Hom.:

AF XY:

0.00796

AC XY:

1082

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0249

Gnomad AMR exome

AF:

0.00758

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.0411

Gnomad SAS exome

AF:

0.00751

Gnomad FIN exome

AF:

0.00929

Gnomad NFE exome

AF:

0.00230

Gnomad OTH exome

AF:

0.00717

GnomAD4 exome

AF:

0.00524

AC:

7662

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

3726

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0275

Gnomad4 AMR exome

AF:

0.00754

Gnomad4 ASJ exome

AF:

0.000918

Gnomad4 EAS exome

AF:

0.0507

Gnomad4 SAS exome

AF:

0.00725

Gnomad4 FIN exome

AF:

0.00876

Gnomad4 NFE exome

AF:

0.00252

Gnomad4 OTH exome

AF:

0.00692

GnomAD4 genome

AF:

0.0107

AC:

1629

AN:

152296

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

786

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0245

Gnomad4 AMR

AF:

0.00686

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.0394

Gnomad4 SAS

AF:

0.00870

Gnomad4 FIN

AF:

0.00650

Gnomad4 NFE

AF:

0.00241

Gnomad4 OTH

AF:

0.00992

Alfa

AF:

0.00608

Hom.:

Bravo

AF:

0.0116

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00142

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

8.1

DANN

Benign

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over