NM_002446.4:c.41C>T

Variant names:

• chr19-40192072-C-T
• rs750965657
• NM_002446.4:c.41C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002446.4(MAP3K10):​c.41C>T​(p.Thr14Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,489,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T14P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: MAP3K10 NM_002446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43
• Publications: 0 publications found

Genes affected

MAP3K10 (HGNC:6849): (mitogen-activated protein kinase kinase kinase 10) The protein encoded by this gene is a member of the serine/threonine kinase family. This kinase has been shown to activate MAPK8/JNK and MKK4/SEK1, and this kinase itself can be phoshorylated, and thus activated by JNK kinases. This kinase functions preferentially on the JNK signaling pathway, and is reported to be involved in nerve growth factor (NGF) induced neuronal apoptosis. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15712696).
• BS2: High AC in GnomAdExome4 at 37 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002446.4. 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
	MAP3K10	NM_002446.4	MANE Select	c.41C>T	p.Thr14Met	missense	Exon 1 of 10	NP_002437.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K10	ENST00000253055.8	TSL:1 MANE Select	c.41C>T	p.Thr14Met	missense	Exon 1 of 10	ENSP00000253055.2	Q02779
	MAP3K10	ENST00000856942.1		c.41C>T	p.Thr14Met	missense	Exon 1 of 10	ENSP00000527002.1
	MAP3K10	ENST00000941194.1		c.41C>T	p.Thr14Met	missense	Exon 1 of 10	ENSP00000611253.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151772 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000981 AC: 1 AN: 101962 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000235

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000276 AC: 37 AN: 1338216 Hom.: 0 Cov.: 33 AF XY: 0.0000214 AC XY: 14 AN XY: 654664

African (AFR) AF: 0.00 AC: 0 AN: 29080

American (AMR) AF: 0.00 AC: 0 AN: 26580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20348

East Asian (EAS) AF: 0.00 AC: 0 AN: 35032

South Asian (SAS) AF: 0.00 AC: 0 AN: 69384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5320

European-Non Finnish (NFE) AF: 0.0000351 AC: 37 AN: 1054252

Other (OTH) AF: 0.00 AC: 0 AN: 55498

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151772 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74100

African (AFR) AF: 0.00 AC: 0 AN: 41314

American (AMR) AF: 0.00 AC: 0 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000869 AC: 1

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	Benign	0.081
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Benign	0.060	T
Sift4G	Uncertain	0.022	D
Polyphen		0.70	P
Vest4		0.18
MutPred		0.27		Loss of glycosylation at T14 (P = 0.0236)
MVP		0.77
MPC		0.90
ClinPred		0.25	T
GERP RS		3.1
Varity_R		0.044
gMVP		0.18
Mutation Taster		=89/11	polymorphism

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: rs750965657; hg19: chr19-40697979;