5-56859851-C-T

Position:

chr5-56859851-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005921.2(MAP3K1):c.770C>T(p.Pro257Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000239 in 1,613,766 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 6 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.61

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:

ENSG00000237705 (HGNC:):

ENSG00000237705 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010439962).

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K1	NM_005921.2 linkuse as main transcript	c.770C>T	p.Pro257Leu	missense_variant	3/20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 linkuse as main transcript	c.770C>T	p.Pro257Leu	missense_variant	3/18		XP_047273174.1
MAP3K1	XM_047417219.1 linkuse as main transcript	c.359C>T	p.Pro120Leu	missense_variant	4/21		XP_047273175.1
MAP3K1	XM_047417220.1 linkuse as main transcript	c.359C>T	p.Pro120Leu	missense_variant	4/21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4 linkuse as main transcript	c.770C>T	p.Pro257Leu	missense_variant	3/20	1	NM_005921.2	ENSP00000382423.3		Q13233
ENSG00000237705	ENST00000415589.1 linkuse as main transcript	n.154G>A		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152164

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:

0.00476

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000543

AC:

135

AN:

248500

Hom.:

AF XY:

0.000720

AC XY:

AN XY:

134794

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:

0.00430

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000664

GnomAD4 exome

AF:

0.000248

AC:

363

AN:

1461484

Hom.:

Cov.:

AF XY:

0.000351

AC XY:

255

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00394

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000144

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74460

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:

0.00435

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000670

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

46,XY sex reversal 6

Pathogenic:1Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	May 14, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	Jul 05, 2021	The c.770C>T variant is not present in publicly available population database like Exome Variant Server (EVS). The variant is present in 1000 Genomes, Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP including homozygotes. The heterozygous state of the variant is present in Indian Exome Database and in our in-house exome database at a low frequency. The variant was earlier reported to ClinVar, as likely pathogenic in similarly affected individuals [PMID: 11242112]. Predictions from different in-silico pathogenicity prediction programs like SIFT, PolyPhen-3, MutationTaster2, CADD, Varsome etc. are contradictory, however these predictions were not proved by established functional studies. Due to lack of enough evidence the variant has been calssified as uncertain significance. -

MAP3K1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2024

The MAP3K1 c.770C>T variant is predicted to result in the amino acid substitution p.Pro257Leu. This variant has been reported in an individual with 46,XY sex reversal (Baxter et al. 2015. PubMed ID: 25383892). This variant is reported at elevated frequencies (0.43% of alleles, including four homozygotes) in individuals of South Asian descent in gnomAD but is rare in other defined subpopulations. Although we suspect that this variant may be benign, the clinical significance of this variant is classified as uncertain at this time due to insufficient functional and genetic evidence. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.3

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.015

Polyphen

0.55

Vest4

0.69

MutPred

0.14

Loss of glycosylation at P257 (P = 0.0347);

MVP

0.57

MPC

0.24

ClinPred

0.48

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.40

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