rs886039236

Positions:

• chr6-90571777-AAAC-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_145331.3(MAP3K7):​c.148_150del​(p.Val50del) variant causes a inframe deletion 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K7 NM_145331.3 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.19

Genes affected

MAP3K7 (HGNC:6859): (mitogen-activated protein kinase kinase kinase 7) The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase mediates the signaling transduction induced by TGF beta and morphogenetic protein (BMP), and controls a variety of cell functions including transcription regulation and apoptosis. In response to IL-1, this protein forms a kinase complex including TRAF6, MAP3K7P1/TAB1 and MAP3K7P2/TAB2; this complex is required for the activation of nuclear factor kappa B. This kinase can also activate MAPK8/JNK, MAP2K4/MKK4, and thus plays a role in the cell response to environmental stresses. Four alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a domain Protein kinase (size 255) in uniprot entity M3K7_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) in NM_145331.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_145331.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-90571777-AAAC-A is Pathogenic according to our data. Variant chr6-90571777-AAAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 264704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K7	NM_145331.3	c.148_150del	p.Val50del	inframe_deletion	2/17	ENST00000369329.8
MAP3K7	NM_003188.4	c.148_150del	p.Val50del	inframe_deletion	2/16
MAP3K7	NM_145332.3	c.148_150del	p.Val50del	inframe_deletion	2/16
MAP3K7	NM_145333.3	c.148_150del	p.Val50del	inframe_deletion	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K7	ENST00000369329.8	c.148_150del	p.Val50del	inframe_deletion	2/17	1	NM_145331.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiospondylocarpofacial syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2020

This variant has been reported to affect MAP3K7 protein function (PMID: 27426734). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with cardiospondylocarpofacial syndrome (PMID: 27426734). It has also been observed to segregate with disease in related individuals. In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 264704). This variant is not present in population databases (ExAC no frequency). This variant, c.148_150del, results in the deletion of 1 amino acid(s) of the MAP3K7 protein (p.Val50del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

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: rs886039236; hg19: chr6-91281496;