Genetic Variant NM_005921.2:c.1687-46C>G (chr5-56874986-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005921.2(MAP3K1):c.1687-46C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0692 in 1,599,424 control chromosomes in the GnomAD database, including 4,073 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 284 hom., cov: 32)

Exomes 𝑓: 0.070 ( 3789 hom. )

Consequence

MAP3K1
NM_005921.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.453

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 5-56874986-C-G is Benign according to our data. Variant chr5-56874986-C-G is described in ClinVar as [Benign]. Clinvar id is 1231698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.1687-46C>G	intron_variant	Intron 9 of 19	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.1687-46C>G	intron_variant	Intron 9 of 17		XP_047273174.1
MAP3K1	XM_047417219.1 link	c.1276-46C>G	intron_variant	Intron 10 of 20		XP_047273175.1
MAP3K1	XM_047417220.1 link	c.1276-46C>G	intron_variant	Intron 10 of 20		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4 link	c.1687-46C>G		intron_variant	Intron 9 of 19	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.0593

AC:

9017

AN:

152122

Hom.:

284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0385

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0569

Gnomad ASJ

AF:

0.0608

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.0570

Gnomad FIN

AF:

0.0740

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0661

Gnomad OTH

AF:

0.0618

GnomAD3 exomes

AF:

0.0664

AC:

16411

AN:

246970

Hom.:

607

AF XY:

0.0662

AC XY:

8868

AN XY:

134038

show subpopulations

Gnomad AFR exome

AF:

0.0358

Gnomad AMR exome

AF:

0.0722

Gnomad ASJ exome

AF:

0.0627

Gnomad EAS exome

AF:

0.104

Gnomad SAS exome

AF:

0.0515

Gnomad FIN exome

AF:

0.0725

Gnomad NFE exome

AF:

0.0663

Gnomad OTH exome

AF:

0.0637

GnomAD4 exome

AF:

0.0702

AC:

101636

AN:

1447184

Hom.:

3789

Cov.:

AF XY:

0.0700

AC XY:

50445

AN XY:

720894

show subpopulations

Gnomad4 AFR exome

AF:

0.0371

Gnomad4 AMR exome

AF:

0.0723

Gnomad4 ASJ exome

AF:

0.0622

Gnomad4 EAS exome

AF:

0.139

Gnomad4 SAS exome

AF:

0.0536

Gnomad4 FIN exome

AF:

0.0740

Gnomad4 NFE exome

AF:

0.0703

Gnomad4 OTH exome

AF:

0.0666

GnomAD4 genome

AF:

0.0592

AC:

9018

AN:

152240

Hom.:

284

Cov.:

AF XY:

0.0596

AC XY:

4433

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0385

Gnomad4 AMR

AF:

0.0568

Gnomad4 ASJ

AF:

0.0608

Gnomad4 EAS

AF:

0.118

Gnomad4 SAS

AF:

0.0564

Gnomad4 FIN

AF:

0.0740

Gnomad4 NFE

AF:

0.0661

Gnomad4 OTH

AF:

0.0612

Alfa

AF:

0.0590

Hom.:

Bravo

AF:

0.0589

Asia WGS

AF:

0.0740

AC:

259

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

46,XY sex reversal 6

Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.86

DANN

Benign

0.23

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