rs387906788

Positions:

• chr5-56856683-T-A
• chr5-56856683-T-C
• chr5-56856683-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP5_Moderate

The NM_005921.2(MAP3K1):​c.566T>A​(p.Leu189Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). 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: Likely pathogenic criteria provided, single submitter P:2
• 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]

(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].
• PP5: Variant 5-56856683-T-A is Pathogenic according to our data. Variant chr5-56856683-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430731.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-56856683-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K1	NM_005921.2	c.566T>A	p.Leu189Gln	missense_variant	2/20	ENST00000399503.4	NP_005912.1
MAP3K1	XM_047417218.1	c.566T>A	p.Leu189Gln	missense_variant	2/18		XP_047273174.1
MAP3K1	XM_047417219.1	c.155T>A	p.Leu52Gln	missense_variant	3/21		XP_047273175.1
MAP3K1	XM_047417220.1	c.155T>A	p.Leu52Gln	missense_variant	3/21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4	c.566T>A	p.Leu189Gln	missense_variant	2/20	1	NM_005921.2	ENSP00000382423	P1
	ENST00000415589.1	n.336+2986A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2015

- -

46,XY sex reversal 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.22	T
Polyphen		0.99	D
Vest4		0.90
MutPred		0.30		Loss of stability (P = 0.0343);
MVP		0.94
MPC		0.87
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.56
gMVP		0.64

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;