10-30439097-T-C

Variant names:

• chr10-30439097-T-C
• rs77186746
• NM_005204.4:c.159T>C

Variant summary

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

The NM_005204.4(MAP3K8):​c.159T>C​(p.Ser53Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,614,200 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (78 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (101 hom.)
• Consequence: MAP3K8 NM_005204.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.74
• Publications: 3 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=-0.86).
• BP6: Variant 10-30439097-T-C is Benign according to our data. Variant chr10-30439097-T-C is described in ClinVar as Benign. ClinVar VariationId is 776503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0584 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005204.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K8	NM_005204.4	MANE Select	c.159T>C	p.Ser53Ser	synonymous	Exon 3 of 9	NP_005195.2
	MAP3K8	NM_001244134.1		c.159T>C	p.Ser53Ser	synonymous	Exon 2 of 8	NP_001231063.1	P41279-1
	MAP3K8	NM_001320961.2		c.159T>C	p.Ser53Ser	synonymous	Exon 2 of 8	NP_001307890.1	P41279-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K8	ENST00000263056.6	TSL:1 MANE Select	c.159T>C	p.Ser53Ser	synonymous	Exon 3 of 9	ENSP00000263056.1	P41279-1
	MAP3K8	ENST00000375321.1	TSL:1	c.159T>C	p.Ser53Ser	synonymous	Exon 1 of 7	ENSP00000364470.1	P41279-1
	MAP3K8	ENST00000542547.5	TSL:1	c.159T>C	p.Ser53Ser	synonymous	Exon 2 of 8	ENSP00000443610.1	P41279-1

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2662 AN: 152194 Hom.: 75 Cov.: 33

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00497 AC: 1250 AN: 251482 AF XY: 0.00368

Gnomad AFR exome AF: 0.0630

Gnomad AMR exome AF: 0.00500

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00200 AC: 2926 AN: 1461888 Hom.: 101 Cov.: 30 AF XY: 0.00175 AC XY: 1274 AN XY: 727244

African (AFR) AF: 0.0668 AC: 2238 AN: 33480

American (AMR) AF: 0.00508 AC: 227 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.000129 AC: 144 AN: 1112010

Other (OTH) AF: 0.00455 AC: 275 AN: 60396

GnomAD4 genome AF: 0.0176 AC: 2676 AN: 152312 Hom.: 78 Cov.: 33 AF XY: 0.0171 AC XY: 1274 AN XY: 74496

African (AFR) AF: 0.0603 AC: 2507 AN: 41556

American (AMR) AF: 0.00758 AC: 116 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68028

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.00743 Hom.: 22

Bravo AF: 0.0205

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.0
DANN	Benign	0.39
PhyloP100		-2.7
PromoterAI		0.018	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs77186746; hg19: chr10-30728026; COSMIC: COSV53919118;