Genetic Variant MAP3K1:p.Arg54Pro (chr5-56815734-G-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005921.2(MAP3K1):c.161G>C(p.Arg54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,347,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3635865).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.161G>C	p.Arg54Pro	missense_variant	Exon 1 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.161G>C	p.Arg54Pro	missense_variant	Exon 1 of 18		XP_047273174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4 link	c.161G>C	p.Arg54Pro	missense_variant	Exon 1 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150722

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000134

AC:

AN:

1197168

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

584416

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000207

GnomAD4 genome

AF:

0.0000199

AC:

AN:

150722

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73560

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000296

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.076

Eigen

Benign

0.090

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.010

REVEL

Benign

0.25

Sift

Uncertain

0.0040

Sift4G

Benign

0.098

Polyphen

0.98

Vest4

0.34

MutPred

0.15

Gain of glycosylation at R54 (P = 0.0443);

MVP

0.60

MPC

0.60

ClinPred

0.63

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over