6-90561637-C-T

Variant names:

• chr6-90561637-C-T
• NM_145331.3:c.328G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_145331.3(MAP3K7):​c.328G>A​(p.Gly110Ser) 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. G110D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K7 NM_145331.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.72

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 12 ACMG points.

• PM1: In a region_of_interest Interaction with MAPK8IP1 (size 299) in uniprot entity M3K7_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_145331.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-90561636-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 6-90561637-C-T is Pathogenic according to our data. Variant chr6-90561637-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2034147.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K7	NM_145331.3	c.328G>A	p.Gly110Ser	missense_variant	Exon 4 of 17	ENST00000369329.8	NP_663304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K7	ENST00000369329.8	c.328G>A	p.Gly110Ser	missense_variant	Exon 4 of 17	1	NM_145331.3	ENSP00000358335.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 14, 2022

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 disrupts the p.Gly110 amino acid residue in MAP3K7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27426734). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with clinical features of cardiospondylocarpofacial Syndrome (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 110 of the MAP3K7 protein (p.Gly110Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.3	M;M;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.90
MutPred		0.95		Loss of catalytic residue at G110 (P = 0.0444);Loss of catalytic residue at G110 (P = 0.0444);Loss of catalytic residue at G110 (P = 0.0444);Loss of catalytic residue at G110 (P = 0.0444);
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-91271356;