3-185447913-C-T

Variant names:

• chr3-185447913-C-T
• rs1185555747
• NM_004721.5:c.976C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004721.5(MAP3K13):​c.976C>T​(p.Arg326Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAP3K13 NM_004721.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07
• Publications: 0 publications found

Genes affected

MAP3K13 (HGNC:6852): (mitogen-activated protein kinase kinase kinase 13) The protein encoded by this gene is a member of serine/threonine protein kinase family. This kinase contains a dual leucine-zipper motif, and has been shown to form dimers/oligomers through its leucine-zipper motif. This kinase can phosphorylate and activate MAPK8/JNK, MAP2K7/MKK7, which suggests a role in the JNK signaling pathway. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004721.5. 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
	MAP3K13	NM_004721.5	MANE Select	c.976C>T	p.Arg326Trp	missense	Exon 5 of 14	NP_004712.1	O43283-1
	MAP3K13	NM_001242314.2		c.976C>T	p.Arg326Trp	missense	Exon 6 of 15	NP_001229243.1	O43283-1
	MAP3K13	NM_001242317.2		c.355C>T	p.Arg119Trp	missense	Exon 4 of 13	NP_001229246.1	O43283-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K13	ENST00000265026.8	TSL:1 MANE Select	c.976C>T	p.Arg326Trp	missense	Exon 5 of 14	ENSP00000265026.3	O43283-1
	MAP3K13	ENST00000424227.5	TSL:1	c.976C>T	p.Arg326Trp	missense	Exon 6 of 15	ENSP00000399910.1	O43283-1
	MAP3K13	ENST00000433092.5	TSL:1	n.*479C>T		non_coding_transcript_exon	Exon 5 of 7	ENSP00000389798.1	O43283-6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459694 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726074

African (AFR) AF: 0.00 AC: 0 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 44136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 85682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111392

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.64		Gain of catalytic residue at P329 (P = 0.0265)
MVP		0.91
MPC		2.1
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.84
gMVP		0.93
Mutation Taster		=40/60	disease causing

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: rs1185555747; hg19: chr3-185165701; COSMIC: COSV99407302; COSMIC: COSV99407302;