chr2-101698129-TC-T

Variant names:

• chr2-101698129-TC-T
• NM_001395002.1:c.52delC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001395002.1(MAP4K4):​c.52delC​(p.Leu18CysfsTer53) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP4K4 NM_001395002.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.88
• Publications: 0 publications found

Genes affected

MAP4K4 (HGNC:6866): (mitogen-activated protein kinase kinase kinase kinase 4) The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase has been shown to specifically activate MAPK8/JNK. The activation of MAPK8 by this kinase is found to be inhibited by the dominant-negative mutants of MAP3K7/TAK1, MAP2K4/MKK4, and MAP2K7/MKK7, which suggests that this kinase may function through the MAP3K7-MAP2K4-MAP2K7 kinase cascade, and mediate the TNF-alpha signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MAP4K4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-101698129-TC-T is Pathogenic according to our data. Variant chr2-101698129-TC-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3340992.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395002.1. 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
	MAP4K4	NM_001395002.1	MANE Select	c.52delC	p.Leu18CysfsTer53	frameshift	Exon 1 of 33	NP_001381931.1	G5E948
	MAP4K4	NM_001384497.1		c.52delC	p.Leu18CysfsTer53	frameshift	Exon 1 of 32	NP_001371426.1
	MAP4K4	NM_001384492.1		c.52delC	p.Leu18CysfsTer53	frameshift	Exon 1 of 33	NP_001371421.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP4K4	ENST00000324219.9	TSL:5 MANE Select	c.52delC	p.Leu18CysfsTer53	frameshift	Exon 1 of 33	ENSP00000313644.6	G5E948
	MAP4K4	ENST00000350878.9	TSL:1	c.52delC	p.Leu18CysfsTer53	frameshift	Exon 1 of 31	ENSP00000343658.5	O95819-6
	MAP4K4	ENST00000347699.8	TSL:1	c.52delC	p.Leu18CysfsTer53	frameshift	Exon 1 of 30	ENSP00000314363.6	O95819-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1104084 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 546202

African (AFR) AF: 0.00 AC: 0 AN: 21810

American (AMR) AF: 0.00 AC: 0 AN: 27952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13956

East Asian (EAS) AF: 0.00 AC: 0 AN: 10662

South Asian (SAS) AF: 0.00 AC: 0 AN: 64164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4070

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 894138

Other (OTH) AF: 0.00 AC: 0 AN: 38082

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9

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

hg19: chr2-102314591;