11-65599621-T-G

Variant names:

• chr11-65599621-T-G
• rs776901400
• NM_002419.4:c.1979A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002419.4(MAP3K11):​c.1979A>C​(p.Asp660Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D660N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K11 NM_002419.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 0 publications found

Genes affected

MAP3K11 (HGNC:6850): (mitogen-activated protein kinase kinase kinase 11) The protein encoded by this gene is a member of the serine/threonine kinase family. This kinase contains a SH3 domain and a leucine zipper-basic motif. This kinase preferentially activates MAPK8/JNK kinase, and functions as a positive regulator of JNK signaling pathway. This kinase can directly phosphorylate, and activates IkappaB kinase alpha and beta, and is found to be involved in the transcription activity of NF-kappaB mediated by Rho family GTPases and CDC42. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.9036 (below the threshold of 3.09). Trascript score misZ: 0.51103 (below the threshold of 3.09).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002419.4. 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
	MAP3K11	NM_002419.4	MANE Select	c.1979A>C	p.Asp660Ala	missense	Exon 9 of 10	NP_002410.1	Q16584-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K11	ENST00000309100.8	TSL:1 MANE Select	c.1979A>C	p.Asp660Ala	missense	Exon 9 of 10	ENSP00000309597.3	Q16584-1
	MAP3K11	ENST00000850884.1		c.1979A>C	p.Asp660Ala	missense	Exon 9 of 10	ENSP00000520962.1
	MAP3K11	ENST00000941368.1		c.1976A>C	p.Asp659Ala	missense	Exon 9 of 10	ENSP00000611427.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.88	P
Vest4		0.49
MutPred		0.34		Gain of MoRF binding (P = 0.0321)
MVP		0.88
MPC		0.21
ClinPred		0.64	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.29
Mutation Taster		=72/28	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: rs776901400; hg19: chr11-65367092;