6-90518552-G-A

Position:

• chr6-90518552-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_145331.3(MAP3K7):​c.1535C>T​(p.Pro512Leu) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P512P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP3K7 NM_145331.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.97

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773
• PP5: Variant 6-90518552-G-A is Pathogenic according to our data. Variant chr6-90518552-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 264698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-90518552-G-A is described in Lovd as [Pathogenic]. Variant chr6-90518552-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K7	NM_145331.3	c.1535C>T	p.Pro512Leu	missense_variant	16/17	ENST00000369329.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K7	ENST00000369329.8	c.1535C>T	p.Pro512Leu	missense_variant	16/17	1	NM_145331.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1414384 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 706048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 10, 2022	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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 264698). This variant is also known as p.Pro485Leu. This missense change has been observed in individual(s) with frontometaphyseal dysplasia (PMID: 27426733). 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 512 of the MAP3K7 protein (p.Pro512Leu). Experimental studies have shown that this missense change affects MAP3K7 function (PMID: 27426733). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2021	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28498505, 27620904, 27426733, 25899317, 29660408, 29467388) -

Frontometaphyseal dysplasia 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 30, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence (ClinVar ID: VCV000264698.10, PS1). The variant has been observed in at least four similarly affected unrelated individuals and reported as de novoo (PMID: 27426733, PS2 and PS4) It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Missense changes are a common disease-causing mechanism (PP2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.802, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.71
MutPred		0.37		.;Loss of disorder (P = 0.018);.;
MVP		0.95
MPC		0.93
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.58
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs886039230; hg19: chr6-91228271;