5-56815617-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005921.2(MAP3K1):c.44C>G(p.Pro15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,312,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.56

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25606436).

BP6

Variant 5-56815617-C-G is Benign according to our data. Variant chr5-56815617-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1033045.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.44C>G	p.Pro15Arg	missense_variant	Exon 1 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.44C>G	p.Pro15Arg	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.44C>G	p.Pro15Arg	missense_variant	Exon 1 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

151212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000236

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000426

AC:

AN:

23490

Hom.:

AF XY:

0.0000681

AC XY:

AN XY:

14684

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00175

GnomAD4 exome

AF:

0.000120

AC:

139

AN:

1160900

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

563282

show subpopulations

Gnomad4 AFR exome

AF:

0.0000848

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000372

Gnomad4 SAS exome

AF:

0.0000698

Gnomad4 FIN exome

AF:

0.0000403

Gnomad4 NFE exome

AF:

0.000133

Gnomad4 OTH exome

AF:

0.0000862

GnomAD4 genome

AF:

0.000119

AC:

AN:

151212

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

73862

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000236

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000309

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

46,XY sex reversal 6

Uncertain:1Benign:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases

Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44C>G (p.P15R) alteration is located in exon 1 (coding exon 1) of the MAP3K1 gene. This alteration results from a C to G substitution at nucleotide position 44, causing the proline (P) at amino acid position 15 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

Benign

0.12

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

Eigen

Benign

0.060

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.53

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.55

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.26

REVEL

Benign

0.10

Sift

Uncertain

0.014

Sift4G

Benign

0.10

Polyphen

0.93

Vest4

0.59

MutPred

0.31

Gain of MoRF binding (P = 9e-04);

MVP

0.57

MPC

0.79

ClinPred

0.22

GERP RS

3.1

Varity_R

0.22

gMVP

0.15

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