rs1042058

Variant names:

• chr10-30439172-T-C
• rs1042058
• NM_005204.4:c.234T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000263056.6(MAP3K8):​c.234T>C​(p.Tyr78Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 1,613,878 control chromosomes in the GnomAD database, including 263,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18559 hom., cov: 33)
  • Exomes 𝑓: 0.57 (244930 hom.)
• Consequence: MAP3K8 ENST00000263056.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.69
• Publications: 76 publications found

Genes affected

MAP3K8 (HGNC:6860): (mitogen-activated protein kinase kinase kinase 8) This gene is an oncogene that encodes a member of the serine/threonine protein kinase family. The encoded protein localizes to the cytoplasm and can activate both the MAP kinase and JNK kinase pathways. This protein was shown to activate IkappaB kinases, and thus induce the nuclear production of NF-kappaB. This protein was also found to promote the production of TNF-alpha and IL-2 during T lymphocyte activation. This gene may also utilize a downstream in-frame translation start codon, and thus produce an isoform containing a shorter N-terminus. The shorter isoform has been shown to display weaker transforming activity. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 10-30439172-T-C is Benign according to our data. Variant chr10-30439172-T-C is described in ClinVar as Benign. ClinVar VariationId is 1174756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000263056.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K8	NM_005204.4	MANE Select	c.234T>C	p.Tyr78Tyr	synonymous	Exon 3 of 9	NP_005195.2
	MAP3K8	NM_001244134.1		c.234T>C	p.Tyr78Tyr	synonymous	Exon 2 of 8	NP_001231063.1
	MAP3K8	NM_001320961.2		c.234T>C	p.Tyr78Tyr	synonymous	Exon 2 of 8	NP_001307890.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K8	ENST00000263056.6	TSL:1 MANE Select	c.234T>C	p.Tyr78Tyr	synonymous	Exon 3 of 9	ENSP00000263056.1
	MAP3K8	ENST00000375321.1	TSL:1	c.234T>C	p.Tyr78Tyr	synonymous	Exon 1 of 7	ENSP00000364470.1
	MAP3K8	ENST00000542547.5	TSL:1	c.234T>C	p.Tyr78Tyr	synonymous	Exon 2 of 8	ENSP00000443610.1

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68768 AN: 151978 Hom.: 18567 Cov.: 33

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.476

GnomAD2 exomes AF: 0.513 AC: 129081 AN: 251414 AF XY: 0.513

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.525

Gnomad EAS exome AF: 0.366

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.604

Gnomad OTH exome AF: 0.541

GnomAD4 exome AF: 0.570 AC: 833223 AN: 1461782 Hom.: 244930 Cov.: 52 AF XY: 0.565 AC XY: 410633 AN XY: 727182

African (AFR) AF: 0.136 AC: 4540 AN: 33480

American (AMR) AF: 0.536 AC: 23957 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 13654 AN: 26134

East Asian (EAS) AF: 0.405 AC: 16097 AN: 39698

South Asian (SAS) AF: 0.359 AC: 30993 AN: 86254

European-Finnish (FIN) AF: 0.612 AC: 32686 AN: 53420

Middle Eastern (MID) AF: 0.446 AC: 2571 AN: 5768

European-Non Finnish (NFE) AF: 0.608 AC: 676250 AN: 1111912

Other (OTH) AF: 0.538 AC: 32475 AN: 60392

GnomAD4 genome AF: 0.452 AC: 68774 AN: 152096 Hom.: 18559 Cov.: 33 AF XY: 0.450 AC XY: 33465 AN XY: 74338

African (AFR) AF: 0.155 AC: 6435 AN: 41526

American (AMR) AF: 0.515 AC: 7866 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1773 AN: 3470

East Asian (EAS) AF: 0.370 AC: 1909 AN: 5162

South Asian (SAS) AF: 0.331 AC: 1598 AN: 4824

European-Finnish (FIN) AF: 0.601 AC: 6350 AN: 10558

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.606 AC: 41178 AN: 67962

Other (OTH) AF: 0.476 AC: 1003 AN: 2108

Alfa AF: 0.551 Hom.: 114267

Bravo AF: 0.432

Asia WGS AF: 0.347 AC: 1207 AN: 3478

EpiCase AF: 0.590

EpiControl AF: 0.588

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.16
DANN	Benign	0.38
PhyloP100		-2.7
PromoterAI		0.014	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042058; hg19: chr10-30728101; COSMIC: COSV53919808; COSMIC: COSV53919808;