chr6-90553473-A-C

Position:

• chr6-90553473-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The ENST00000369329.8(MAP3K7):​c.721T>G​(p.Trp241Gly) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W241R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K7 ENST00000369329.8 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.29

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 10 ACMG points.

• PM1: In a domain Protein kinase (size 255) in uniprot entity M3K7_HUMAN there are 29 pathogenic changes around while only 6 benign (83%) in ENST00000369329.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-90553473-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 264705.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 6-90553473-A-C is Pathogenic according to our data. Variant chr6-90553473-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 423266.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K7	NM_145331.3	c.721T>G	p.Trp241Gly	missense_variant	7/17	ENST00000369329.8	NP_663304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K7	ENST00000369329.8	c.721T>G	p.Trp241Gly	missense_variant	7/17	1	NM_145331.3	ENSP00000358335	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2018	The W241G variant in the MAP3K7 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, a variant at the same residue, W241R, has been reported in an individual with cardiospondylocarpofacial syndrome (Le Goff et al., 2016). The W241G variant is not observed in large population cohorts (Lek et al., 2016). The W241G variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret W241G as a pathogenic variant. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as pathogenic and reported on 07/05/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.88	.;.;.;D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.2	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-12	D;D;D;D
REVEL	Pathogenic	0.80
Sift	Benign	0.11	T;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;P;P;B
Vest4		0.85
MutPred		0.69		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.98
MPC		3.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.90
gMVP		0.89

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: rs886039237; hg19: chr6-91263192;