5-56872885-C-T

Variant names:

• chr5-56872885-C-T
• rs2229882
• NM_005921.2:c.1566C>T

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.1566C>T​(p.Thr522Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0529 in 1,613,946 control chromosomes in the GnomAD database, including 2,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (158 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2270 hom.)
• Consequence: MAP3K1 NM_005921.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0540
• Publications: 27 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=-0.78).
• BP6: Variant 5-56872885-C-T is Benign according to our data. Variant chr5-56872885-C-T is described in ClinVar as Benign. ClinVar VariationId is 471689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.054 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0558 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.1566C>T	p.Thr522Thr	synonymous	Exon 9 of 20	NP_005912.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.1566C>T	p.Thr522Thr	synonymous	Exon 9 of 20	ENSP00000382423.3
	MAP3K1	ENST00000872825.1		c.1560C>T	p.Thr520Thr	synonymous	Exon 9 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.1365C>T	p.Thr455Thr	synonymous	Exon 8 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes AF: 0.0442 AC: 6728 AN: 152170 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0506

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.0610

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0518

Gnomad OTH AF: 0.0497

GnomAD2 exomes AF: 0.0483 AC: 12045 AN: 249186 AF XY: 0.0472

Gnomad AFR exome AF: 0.0302

Gnomad AMR exome AF: 0.0682

Gnomad ASJ exome AF: 0.0586

Gnomad EAS exome AF: 0.0557

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.0527

Gnomad OTH exome AF: 0.0461

GnomAD4 exome AF: 0.0538 AC: 78683 AN: 1461658 Hom.: 2270 Cov.: 32 AF XY: 0.0531 AC XY: 38640 AN XY: 727124

African (AFR) AF: 0.0317 AC: 1061 AN: 33478

American (AMR) AF: 0.0683 AC: 3055 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0584 AC: 1527 AN: 26134

East Asian (EAS) AF: 0.0658 AC: 2610 AN: 39686

South Asian (SAS) AF: 0.0281 AC: 2426 AN: 86252

European-Finnish (FIN) AF: 0.0290 AC: 1551 AN: 53410

Middle Eastern (MID) AF: 0.0271 AC: 156 AN: 5766

European-Non Finnish (NFE) AF: 0.0569 AC: 63248 AN: 1111830

Other (OTH) AF: 0.0505 AC: 3049 AN: 60386

GnomAD4 genome AF: 0.0442 AC: 6728 AN: 152288 Hom.: 158 Cov.: 32 AF XY: 0.0430 AC XY: 3206 AN XY: 74472

African (AFR) AF: 0.0321 AC: 1335 AN: 41552

American (AMR) AF: 0.0505 AC: 773 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 201 AN: 3472

East Asian (EAS) AF: 0.0613 AC: 318 AN: 5188

South Asian (SAS) AF: 0.0304 AC: 147 AN: 4828

European-Finnish (FIN) AF: 0.0275 AC: 292 AN: 10604

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0518 AC: 3526 AN: 68026

Other (OTH) AF: 0.0491 AC: 104 AN: 2116

Alfa AF: 0.0502 Hom.: 420

Bravo AF: 0.0473

Asia WGS AF: 0.0400 AC: 139 AN: 3478

EpiCase AF: 0.0522

EpiControl AF: 0.0579

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	-0.78
CADD	Benign	4.1
DANN	Benign	0.33
PhyloP100		0.054
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2229882; hg19: chr5-56168712; COSMIC: COSV68121965;