rs863225437

Positions:

• chr2-173232359-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_016653.3(MAP3K20):​c.1103T>G​(p.Phe368Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAP3K20 NM_016653.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.77

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-AS1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 2-173232359-T-G is Pathogenic according to our data. Variant chr2-173232359-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 218144.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K20	NM_016653.3	c.1103T>G	p.Phe368Cys	missense_variant	14/20	ENST00000375213.8	NP_057737.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K20	ENST00000375213.8	c.1103T>G	p.Phe368Cys	missense_variant	14/20	1	NM_016653.3	ENSP00000364361.3
MAP3K20	ENST00000409176.6	c.1103T>G	p.Phe368Cys	missense_variant	14/20	1		ENSP00000387259.2
MAP3K20-AS1	ENST00000423106.2	n.464-16523A>C		intron_variant		1
MAP3K20-AS1	ENST00000422703.5	n.111-24701A>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Split hand-foot malformation 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Max Planck Institute for Molecular Genetics

Nov 18, 2015

Pathogenic. Mouse models confirms pathogenicity of variant. -

Split-foot malformation-mesoaxial polydactyly syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.66	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.74
MutPred		0.85		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.77
MPC		1.8
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.65
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs863225437; hg19: chr2-174097087;