5-56882284-A-G

Variant names:

• chr5-56882284-A-G
• rs3822625
• NM_005921.2:c.3084A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005921.2(MAP3K1):​c.3084A>G​(p.Gln1028Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0732 in 1,614,018 control chromosomes in the GnomAD database, including 4,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (502 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4071 hom.)
• Consequence: MAP3K1 NM_005921.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.39
• Publications: 26 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, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.56).
• BP6: Variant 5-56882284-A-G is Benign according to our data. Variant chr5-56882284-A-G is described in ClinVar as Benign. ClinVar VariationId is 1170263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.39 with no splicing effect.
• 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.3084A>G	p.Gln1028Gln	synonymous	Exon 14 of 20	NP_005912.1	Q13233

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.3084A>G	p.Gln1028Gln	synonymous	Exon 14 of 20	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.3078A>G	p.Gln1026Gln	synonymous	Exon 14 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.2883A>G	p.Gln961Gln	synonymous	Exon 13 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes AF: 0.0789 AC: 11993 AN: 152080 Hom.: 499 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0670

Gnomad ASJ AF: 0.0677

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0571

Gnomad FIN AF: 0.0740

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0667

Gnomad OTH AF: 0.0822

GnomAD2 exomes AF: 0.0720 AC: 17926 AN: 248996 AF XY: 0.0705

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0759

Gnomad ASJ exome AF: 0.0725

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.0725

Gnomad NFE exome AF: 0.0669

Gnomad OTH exome AF: 0.0659

GnomAD4 exome AF: 0.0726 AC: 106135 AN: 1461820 Hom.: 4071 Cov.: 63 AF XY: 0.0721 AC XY: 52449 AN XY: 727204

African (AFR) AF: 0.104 AC: 3477 AN: 33480

American (AMR) AF: 0.0763 AC: 3412 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0699 AC: 1828 AN: 26136

East Asian (EAS) AF: 0.139 AC: 5514 AN: 39696

South Asian (SAS) AF: 0.0537 AC: 4635 AN: 86258

European-Finnish (FIN) AF: 0.0740 AC: 3949 AN: 53398

Middle Eastern (MID) AF: 0.0498 AC: 287 AN: 5768

European-Non Finnish (NFE) AF: 0.0707 AC: 78660 AN: 1111984

Other (OTH) AF: 0.0724 AC: 4373 AN: 60394

GnomAD4 genome AF: 0.0789 AC: 12004 AN: 152198 Hom.: 502 Cov.: 32 AF XY: 0.0786 AC XY: 5850 AN XY: 74410

African (AFR) AF: 0.104 AC: 4325 AN: 41512

American (AMR) AF: 0.0668 AC: 1022 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0677 AC: 235 AN: 3470

East Asian (EAS) AF: 0.117 AC: 607 AN: 5170

South Asian (SAS) AF: 0.0565 AC: 273 AN: 4830

European-Finnish (FIN) AF: 0.0740 AC: 784 AN: 10598

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0667 AC: 4533 AN: 68010

Other (OTH) AF: 0.0814 AC: 172 AN: 2114

Alfa AF: 0.0702 Hom.: 1275

Bravo AF: 0.0814

Asia WGS AF: 0.0810 AC: 281 AN: 3478

EpiCase AF: 0.0669

EpiControl AF: 0.0689

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.1
DANN	Benign	0.56
PhyloP100		1.4
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: rs3822625; hg19: chr5-56178111; COSMIC: COSV68121972; COSMIC: COSV68121972;