5-56856683-T-G

Variant names:

• chr5-56856683-T-G
• rs387906788
• NM_005921.2:c.566T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_005921.2(MAP3K1):​c.566T>G​(p.Leu189Arg) variant causes a missense change. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L189P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.79

Genes affected

MAP3K1 (HGNC:6848): (mitogen-activated protein kinase kinase kinase 1) The protein encoded by this gene is a serine/threonine kinase and is part of some signal transduction cascades, including the ERK and JNK kinase pathways as well as the NF-kappa-B pathway. The encoded protein is activated by autophosphorylation and requires magnesium as a cofactor in phosphorylating other proteins. This protein has E3 ligase activity conferred by a plant homeodomain (PHD) in its N-terminus and phospho-kinase activity conferred by a kinase domain in its C-terminus. [provided by RefSeq, Mar 2012]

ENSG00000237705 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-56856683-T-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763
• PP5: Variant 5-56856683-T-G is Pathogenic according to our data. Variant chr5-56856683-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 30147.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-56856683-T-G is described in Lovd as [Likely_pathogenic]. Variant chr5-56856683-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2	c.566T>G	p.Leu189Arg	missense_variant	Exon 2 of 20	ENST00000399503.4	NP_005912.1
MAP3K1	XM_047417218.1	c.566T>G	p.Leu189Arg	missense_variant	Exon 2 of 18		XP_047273174.1
MAP3K1	XM_047417219.1	c.155T>G	p.Leu52Arg	missense_variant	Exon 3 of 21		XP_047273175.1
MAP3K1	XM_047417220.1	c.155T>G	p.Leu52Arg	missense_variant	Exon 3 of 21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4	c.566T>G	p.Leu189Arg	missense_variant	Exon 2 of 20	1	NM_005921.2	ENSP00000382423.3
ENSG00000237705	ENST00000415589.1	n.336+2986A>C		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

46,XY sex reversal 6 Pathogenic:1

Dec 10, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.063	T
Polyphen		0.99	D
Vest4		0.93
MutPred		0.34		Loss of stability (P = 0.0203);
MVP		0.98
MPC		1.0
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.67
gMVP		0.70

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: rs387906788; hg19: chr5-56152510;