chr6-90571777-AAAC-A

Variant names:

• chr6-90571777-AAAC-A
• rs886039236
• NM_145331.3:c.148_150delGTT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_145331.3(MAP3K7):​c.148_150delGTT​(p.Val50del) variant causes a conservative 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 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.19
• Publications: 1 publications found

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]

MAP3K7 Gene-Disease associations (from GenCC):

• cardiospondylocarpofacial syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• frontometaphyseal dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet
• frontometaphyseal dysplasia 2

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• 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 VariationId is 264704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145331.3. 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
	MAP3K7	NM_145331.3	MANE Select	c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 17	NP_663304.1	O43318-1
	MAP3K7	NM_003188.4		c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 16	NP_003179.1	O43318-2
	MAP3K7	NM_145332.3		c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 16	NP_663305.1	O43318-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K7	ENST00000369329.8	TSL:1 MANE Select	c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 17	ENSP00000358335.3	O43318-1
	MAP3K7	ENST00000369332.7	TSL:1	c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 16	ENSP00000358338.3	O43318-2
	MAP3K7	ENST00000369325.7	TSL:1	c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 16	ENSP00000358331.3	O43318-3

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Cardiospondylocarpofacial syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=42/58	disease causing (ClinVar)

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

dbSNP: rs886039236; hg19: chr6-91281496; COSMIC: COSV100997942;