5-56856683-T-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_005921.2(MAP3K1):​c.566T>C​(p.Leu189Pro) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L189R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.79
• Publications: 13 publications found

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]

MAP3K1 Gene-Disease associations (from GenCC):

• 46,XY sex reversal 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• 46,XY complete gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000237705 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30147.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794
• PP5: Variant 5-56856683-T-C is Pathogenic according to our data. Variant chr5-56856683-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30146.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005921.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	NM_005921.2	MANE Select	c.566T>C	p.Leu189Pro	missense	Exon 2 of 20	NP_005912.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.566T>C	p.Leu189Pro	missense	Exon 2 of 20	ENSP00000382423.3
	ENSG00000237705	ENST00000415589.1	TSL:3	n.336+2986A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

MAP3K1-related disorder Pathogenic:1

May 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MAP3K1 c.566T>C variant is predicted to result in the amino acid substitution p.Leu189Pro. This variant has been previously reported in an individual with 46,XY complete gonadal dysgenesis (Pearlman et al. 2010. PubMed ID: 21129722). Functional studies support its pathogenicity (Loke and Ostrer. 2012. PubMed ID: 22171599; Upadhyay et al. 2018. PubMed ID: 29095481; Chamberlin et al. 2019. PubMed ID: 30608580). Alternative nucleotide changes affecting the same amino acid (p.Leu189Arg and p.Leu189Gln) have also been reported in unrelated individuals with disorders of sex development (Pearlman et al. 2010. PubMed ID: 21129722; Granados et al. 2017. PubMed ID: 28504475). The c.566T>C (p.Leu189Pro) variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In summary, this variant is interpreted as pathogenic.

46,XY sex reversal 6 Pathogenic:1

Dec 10, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.068	T
Polyphen		1.0	D
Vest4		0.98
MutPred		0.47		Loss of stability (P = 0.0086)
MVP		0.97
MPC		1.1
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.74
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906788; hg19: chr5-56152510;