rs56160159

Positions:

• chr5-56859851-C-A
• chr5-56859851-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_005921.2(MAP3K1):​c.770C>A​(p.Pro257Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P257L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.61

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-56859851-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.29151076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K1	NM_005921.2	c.770C>A	p.Pro257Gln	missense_variant	3/20	ENST00000399503.4	NP_005912.1
MAP3K1	XM_047417218.1	c.770C>A	p.Pro257Gln	missense_variant	3/18		XP_047273174.1
MAP3K1	XM_047417219.1	c.359C>A	p.Pro120Gln	missense_variant	4/21		XP_047273175.1
MAP3K1	XM_047417220.1	c.359C>A	p.Pro120Gln	missense_variant	4/21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4	c.770C>A	p.Pro257Gln	missense_variant	3/20	1	NM_005921.2	ENSP00000382423.3
ENSG00000237705	ENST00000415589.1	n.154G>T		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.81	P
Vest4		0.28
MutPred		0.16		Loss of glycosylation at P257 (P = 0.0347);
MVP		0.57
MPC		0.29
ClinPred		0.57	D
GERP RS		5.7
Varity_R		0.22
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-56155678; COSMIC: COSV101266505;