Variant chr5-56815758-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005921.2(MAP3K1):c.185T>G(p.Leu62Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000624 in 1,377,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42

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 -4 ACMG points.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K1	NM_005921.2 linkuse as main transcript	c.185T>G	p.Leu62Arg	missense_variant	1/20	ENST00000399503.4
MAP3K1	XM_047417218.1 linkuse as main transcript	c.185T>G	p.Leu62Arg	missense_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K1	ENST00000399503.4 linkuse as main transcript	c.185T>G	p.Leu62Arg	missense_variant	1/20	1	NM_005921.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0000795

AC:

AN:

150966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

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:

0.000104

Gnomad OTH

AF:

0.000962

GnomAD3 exomes

AF:

0.0000423

AC:

AN:

70960

Hom.:

AF XY:

0.0000243

AC XY:

AN XY:

41198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000764

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000381

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.0000603

AC:

AN:

1226600

Hom.:

Cov.:

AF XY:

0.0000549

AC XY:

AN XY:

600994

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000434

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:

0.0000664

Gnomad4 OTH exome

AF:

0.000141

GnomAD4 genome

AF:

0.0000795

AC:

AN:

150966

Hom.:

Cov.:

AF XY:

0.0000950

AC XY:

AN XY:

73712

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000104

Gnomad4 OTH

AF:

0.000962

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000102

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The c.185T>G (p.L62R) alteration is located in exon 1 (coding exon 1) of the MAP3K1 gene. This alteration results from a T to G substitution at nucleotide position 185, causing the leucine (L) at amino acid position 62 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.089

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.87

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.34

MutationTaster

Benign

0.61

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.29

REVEL

Benign

0.19

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

0.0

Vest4

0.55

MutPred

0.26

Gain of solvent accessibility (P = 0.0584);

MVP

0.65

MPC

0.85

ClinPred

0.22

GERP RS

2.5

Varity_R

0.50

gMVP

0.20

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over