rs16886448

Variant names:

• chr5-56874986-C-G
• rs16886448
• NM_005921.2:c.1687-46C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-56874986-C-G
• chr5-56874986-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.453
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• 46,XY sex reversal 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• 46,XY complete gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005921.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	NM_005921.2	MANE Select	c.1687-46C>G		intron	N/A	NP_005912.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.1687-46C>G		intron	N/A	ENSP00000382423.3
	MAP3K1	ENST00000872825.1		c.1681-46C>G		intron	N/A	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.1486-46C>G		intron	N/A	ENSP00000618718.1

Frequencies

GnomAD3 genomes AF: 0.0593 AC: 9017 AN: 152122 Hom.: 284 Cov.: 32

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

GnomAD2 exomes AF: 0.0664 AC: 16411 AN: 246970 AF XY: 0.0662

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 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.: 29 AF XY: 0.0700 AC XY: 50445 AN XY: 720894

African (AFR) AF: 0.0371 AC: 1232 AN: 33186

American (AMR) AF: 0.0723 AC: 3230 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 1620 AN: 26040

East Asian (EAS) AF: 0.139 AC: 5501 AN: 39632

South Asian (SAS) AF: 0.0536 AC: 4606 AN: 85894

European-Finnish (FIN) AF: 0.0740 AC: 3954 AN: 53406

Middle Eastern (MID) AF: 0.0397 AC: 227 AN: 5722

European-Non Finnish (NFE) AF: 0.0703 AC: 77276 AN: 1098680

Other (OTH) AF: 0.0666 AC: 3990 AN: 59920

GnomAD4 genome AF: 0.0592 AC: 9018 AN: 152240 Hom.: 284 Cov.: 32 AF XY: 0.0596 AC XY: 4433 AN XY: 74418

African (AFR) AF: 0.0385 AC: 1600 AN: 41558

American (AMR) AF: 0.0568 AC: 869 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 211 AN: 3468

East Asian (EAS) AF: 0.118 AC: 610 AN: 5184

South Asian (SAS) AF: 0.0564 AC: 272 AN: 4822

European-Finnish (FIN) AF: 0.0740 AC: 783 AN: 10580

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0661 AC: 4493 AN: 68014

Other (OTH) AF: 0.0612 AC: 129 AN: 2108

Alfa AF: 0.0590 Hom.: 39

Bravo AF: 0.0589

Asia WGS AF: 0.0740 AC: 259 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	46,XY sex reversal 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.86
DANN	Benign	0.23
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16886448; hg19: chr5-56170813; COSMIC: COSV68128864;