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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• frontometaphyseal dysplasia

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

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K7	NM_145331.3	c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 17	ENST00000369329.8	NP_663304.1
MAP3K7	NM_003188.4	c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 16		NP_003179.1
MAP3K7	NM_145332.3	c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 16		NP_663305.1
MAP3K7	NM_145333.3	c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 15		NP_663306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K7	ENST00000369329.8	c.148_150delGTT	p.Val50del	conservative_inframe_deletion	Exon 2 of 17	1	NM_145331.3	ENSP00000358335.3

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

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiospondylocarpofacial syndrome Pathogenic:2

Feb 04, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect MAP3K7 protein function (PMID: 27426734). 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

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;