5-56864915-G-A

Position:

• chr5-56864915-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_005921.2(MAP3K1):​c.1016G>A​(p.Arg339Gln) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 5-56864915-G-A is Pathogenic according to our data. Variant chr5-56864915-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 471688.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-56864915-G-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.1016G>A	p.Arg339Gln	missense_variant	4/20	ENST00000399503.4	NP_005912.1
MAP3K1	XM_047417218.1	c.1016G>A	p.Arg339Gln	missense_variant	4/18		XP_047273174.1
MAP3K1	XM_047417219.1	c.605G>A	p.Arg202Gln	missense_variant	5/21		XP_047273175.1
MAP3K1	XM_047417220.1	c.605G>A	p.Arg202Gln	missense_variant	5/21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4	c.1016G>A	p.Arg339Gln	missense_variant	4/20	1	NM_005921.2	ENSP00000382423.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2022

For these reasons, this variant has been classified as Pathogenic. 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: 471688). This missense change has been observed in individual(s) with clinical features of 46,XY disorder of sex development (PMID: 25383892; 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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 339 of the MAP3K1 protein (p.Arg339Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.82	N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.94
MutPred		0.72		Loss of ubiquitination at K337 (P = 0.0837);
MVP		0.84
MPC		0.83
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.38
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1554034036; hg19: chr5-56160742; COSMIC: COSV105336092; COSMIC: COSV105336092;