chr2-173182905-A-C

Position:

• chr2-173182905-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016653.3(MAP3K20):​c.299A>C​(p.Glu100Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,756 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: 6.9e-7 (0 hom.)
• Consequence: MAP3K20 NM_016653.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.92

Genes affected

MAP3K20 (HGNC:17797): (mitogen-activated protein kinase kinase kinase 20) This gene is a member of the MAPKKK family of signal transduction molecules and encodes a protein with an N-terminal kinase catalytic domain, followed by a leucine zipper motif and a sterile-alpha motif (SAM). This magnesium-binding protein forms homodimers and is located in the cytoplasm. The protein mediates gamma radiation signaling leading to cell cycle arrest and activity of this protein plays a role in cell cycle checkpoint regulation in cells. The protein also has pro-apoptotic activity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

MAP3K20 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K20	NM_016653.3	c.299A>C	p.Glu100Ala	missense_variant	4/20	ENST00000375213.8	NP_057737.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K20	ENST00000375213.8	c.299A>C	p.Glu100Ala	missense_variant	4/20	1	NM_016653.3	ENSP00000364361.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458756 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725444

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: 9.00e-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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 12, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 100 of the MAP3K20 protein (p.Glu100Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MAP3K20-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;T;.;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;.;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Uncertain	0.045	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N;N;N;N;D
REVEL	Uncertain	0.42
Sift	Benign	0.19	T;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.26	B;P;B;P;.
Vest4		0.54
MutPred		0.31		Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);
MVP		0.47
MPC		1.5
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.69
gMVP		0.54

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: chr2-174047633;