6-136567644-T-C

Position:

• chr6-136567644-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005923.4(MAP3K5):​c.3748A>G​(p.Ile1250Val) variant causes a missense change. The variant allele was found at a frequency of 0.000948 in 1,613,808 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00085 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (22 hom.)
• Consequence: MAP3K5 NM_005923.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.06

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005425483).
• BP6: Variant 6-136567644-T-C is Benign according to our data. Variant chr6-136567644-T-C is described in ClinVar as [Benign]. Clinvar id is 736322.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000847 (129/152326) while in subpopulation EAS AF= 0.022 (114/5190). AF 95% confidence interval is 0.0187. There are 3 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 129 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.3748A>G	p.Ile1250Val	missense_variant	26/30	ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.3748A>G	p.Ile1250Val	missense_variant	26/30	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.4075A>G	p.Ile1359Val	missense_variant	27/31			ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152208 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0219

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00185 AC: 465 AN: 250744 Hom.: 5 AF XY: 0.00179 AC XY: 243 AN XY: 135472

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.0238

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000959 AC: 1401 AN: 1461482 Hom.: 22 Cov.: 31 AF XY: 0.000900 AC XY: 654 AN XY: 726996

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.000460

Gnomad4 EAS exome AF: 0.0318

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152326 Hom.: 3 Cov.: 32 AF XY: 0.000993 AC XY: 74 AN XY: 74502

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.0220

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00131 Hom.: 2

Bravo AF: 0.00109

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00179 AC: 217

Asia WGS AF: 0.0100 AC: 36 AN: 3478

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.0096
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.099
Sift	Benign	0.41	T
Sift4G	Benign	0.29	T
Polyphen		0.022	B
Vest4		0.15
MVP		0.60
MPC		0.33
ClinPred		0.015	T
GERP RS		5.6
Varity_R		0.043
gMVP		0.027

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: rs35551087; hg19: chr6-136888782; COSMIC: COSV62890415;