6-136583645-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_005923.4(MAP3K5):c.3321C>T(p.Ala1107=) 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.05

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]

ACMG classification

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 GnomAd at 1611 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K5	NM_005923.4	c.3321C>T	p.Ala1107=	synonymous_variant	24/30	ENST00000359015.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K5	ENST00000359015.5	c.3321C>T	p.Ala1107=	synonymous_variant	24/30	1	NM_005923.4	P1
MAP3K5	ENST00000698928.1	c.3648C>T	p.Ala1216=	synonymous_variant	25/31
MAP3K5	ENST00000463140.1	n.202C>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1611 AN: 152178 Hom.: 18 Cov.: 32

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.: 27 AF XY: 0.00796 AC XY: 1082 AN XY: 135872

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.: 93 Cov.: 31 AF XY: 0.00512 AC XY: 3726 AN XY: 727228

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.: 19 Cov.: 32 AF XY: 0.0106 AC XY: 786 AN XY: 74474

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.: 7

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

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2018

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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

Other links and lift over

dbSNP: rs78692210; hg19: chr6-136904783; COSMIC: COSV62891375;