11-65599621-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002419.4(MAP3K11):​c.1979A>G​(p.Asp660Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• 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 2 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).
• BP4: Computational evidence support a benign effect (MetaRNN=0.41992298).

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>G	p.Asp660Gly	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>G	p.Asp660Gly	missense	Exon 9 of 10	ENSP00000309597.3	Q16584-1
	MAP3K11	ENST00000850884.1		c.1979A>G	p.Asp660Gly	missense	Exon 9 of 10	ENSP00000520962.1
	MAP3K11	ENST00000941368.1		c.1976A>G	p.Asp659Gly	missense	Exon 9 of 10	ENSP00000611427.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000662 AC: 1 AN: 151018 AF XY: 0.0000117

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000450

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388698 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 687494

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29092

American (AMR) AF: 0.0000301 AC: 1 AN: 33228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23752

East Asian (EAS) AF: 0.00 AC: 0 AN: 35820

South Asian (SAS) AF: 0.00 AC: 0 AN: 79716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4142

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080862

Other (OTH) AF: 0.00 AC: 0 AN: 57142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000935 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.054	T
Polyphen		0.88	P
Vest4		0.48
MutPred		0.33		Gain of MoRF binding (P = 0.0421)
MVP		0.89
MPC		0.25
ClinPred		0.48	T
GERP RS		5.1
Varity_R		0.35
gMVP		0.27
Mutation Taster		=71/29	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;