rs2229883

Variant names:

• chr5-56875262-G-A
• rs2229883
• NM_005921.2:c.1917G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-56875262-G-A
• chr5-56875262-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005921.2(MAP3K1):​c.1917G>A​(p.Leu639Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,132 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (10 hom.)
• Consequence: MAP3K1 NM_005921.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.401
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 5-56875262-G-A is Benign according to our data. Variant chr5-56875262-G-A is described in ClinVar as Benign. ClinVar VariationId is 539065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.401 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00733 (1116/152292) while in subpopulation AFR AF = 0.0242 (1005/41548). AF 95% confidence interval is 0.0229. There are 21 homozygotes in GnomAd4. There are 525 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1116 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	NM_005921.2	MANE Select	c.1917G>A	p.Leu639Leu	synonymous	Exon 10 of 20	NP_005912.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.1917G>A	p.Leu639Leu	synonymous	Exon 10 of 20	ENSP00000382423.3

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1114 AN: 152174 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00237 AC: 591 AN: 249292 AF XY: 0.00171

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00113 AC: 1653 AN: 1461840 Hom.: 10 Cov.: 32 AF XY: 0.000991 AC XY: 721 AN XY: 727220

African (AFR) AF: 0.0265 AC: 886 AN: 33480

American (AMR) AF: 0.00195 AC: 87 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00348 AC: 91 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53416

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5746

European-Non Finnish (NFE) AF: 0.000382 AC: 425 AN: 1112002

Other (OTH) AF: 0.00237 AC: 143 AN: 60386

GnomAD4 genome AF: 0.00733 AC: 1116 AN: 152292 Hom.: 21 Cov.: 32 AF XY: 0.00705 AC XY: 525 AN XY: 74478

African (AFR) AF: 0.0242 AC: 1005 AN: 41548

American (AMR) AF: 0.00432 AC: 66 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00361 Hom.: 5

Bravo AF: 0.00841

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.3
DANN	Benign	0.68
PhyloP100		0.40
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2229883; hg19: chr5-56171089; COSMIC: COSV68126649;