3-185463554-A-C

Position:

• chr3-185463554-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004721.5(MAP3K13):​c.1283A>C​(p.Glu428Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MAP3K13 NM_004721.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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]

LOC124906312 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MAP3K13

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K13	NM_004721.5	c.1283A>C	p.Glu428Ala	missense_variant	8/14	ENST00000265026.8
LOC124906312	XR_007096202.1	n.4273-2689T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K13	ENST00000265026.8	c.1283A>C	p.Glu428Ala	missense_variant	8/14	1	NM_004721.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1429708 Hom.: 0 Cov.: 26 AF XY: 0.00000140 AC XY: 1 AN XY: 712932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.1283A>C (p.E428A) alteration is located in exon 8 (coding exon 7) of the MAP3K13 gene. This alteration results from a A to C substitution at nucleotide position 1283, causing the glutamic acid (E) at amino acid position 428 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Benign	0.95
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.4	N;D;N;D;N
REVEL	Uncertain	0.57
Sift	Benign	0.030	D;D;D;D;T
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.58	P;P;P;P;.
Vest4		0.73
MutPred		0.45		.;Gain of catalytic residue at E428 (P = 0.0423);.;Gain of catalytic residue at E428 (P = 0.0423);.;
MVP		0.94
MPC		0.99
ClinPred		0.86	D
GERP RS		5.8
Varity_R		0.39
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-185181342;