2-173182886-A-AT

Variant names:

• chr2-173182886-A-AT
• rs1553576774
• NM_016653.3:c.282dupT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_016653.3(MAP3K20):​c.282dupT​(p.Asn95fs) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K20 NM_016653.3 frameshift, stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.68
• Publications: 0 publications found

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:27935): (MAP3K20 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-173182886-A-AT is Pathogenic according to our data. Variant chr2-173182886-A-AT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 446160.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016653.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K20	NM_016653.3	MANE Select	c.282dupT	p.Asn95fs	frameshift stop_gained	Exon 4 of 20	NP_057737.2
	MAP3K20	NM_133646.3		c.282dupT	p.Asn95fs	frameshift stop_gained	Exon 4 of 12	NP_598407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K20	ENST00000375213.8	TSL:1 MANE Select	c.282dupT	p.Asn95fs	frameshift stop_gained	Exon 4 of 20	ENSP00000364361.3
	MAP3K20	ENST00000409176.6	TSL:1	c.282dupT	p.Asn95fs	frameshift stop_gained	Exon 4 of 20	ENSP00000387259.2
	MAP3K20	ENST00000338983.7	TSL:1	c.282dupT	p.Asn95fs	frameshift stop_gained	Exon 4 of 12	ENSP00000340257.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Split-foot malformation-mesoaxial polydactyly syndrome Pathogenic:1

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team

Myopathy, centronuclear, 6, with fiber-type disproportion Pathogenic:1

Jul 28, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=48/252	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1553576774; hg19: chr2-174047614;