chr6-90556605-C-G

Variant names:

• chr6-90556605-C-G
• rs886039233
• NM_145331.3:c.502G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_145331.3(MAP3K7):​c.502G>C​(p.Gly168Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G168G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K7 NM_145331.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.90
• Publications: 3 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804
• PP5: Variant 6-90556605-C-G is Pathogenic according to our data. Variant chr6-90556605-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 264701.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K7	NM_145331.3	MANE Select	c.502G>C	p.Gly168Arg	missense	Exon 6 of 17	NP_663304.1
	MAP3K7	NM_003188.4		c.502G>C	p.Gly168Arg	missense	Exon 6 of 16	NP_003179.1
	MAP3K7	NM_145332.3		c.502G>C	p.Gly168Arg	missense	Exon 6 of 16	NP_663305.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K7	ENST00000369329.8	TSL:1 MANE Select	c.502G>C	p.Gly168Arg	missense	Exon 6 of 17	ENSP00000358335.3
	MAP3K7	ENST00000369332.7	TSL:1	c.502G>C	p.Gly168Arg	missense	Exon 6 of 16	ENSP00000358338.3
	MAP3K7	ENST00000369325.7	TSL:1	c.502G>C	p.Gly168Arg	missense	Exon 6 of 16	ENSP00000358331.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Frontometaphyseal dysplasia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.44
Sift	Benign	0.034	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.59		Gain of solvent accessibility (P = 0.0674)
MVP		0.79
MPC		2.8
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.93
Mutation Taster		=0/100	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: rs886039233; hg19: chr6-91266324;