5-56882021-TCAACAACAACAACAA-TCAACAACAACAA

Variant names:

• chr5-56882021-TCAA-T
• rs5868032
• NM_005921.2:c.2845_2847delACA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005921.2(MAP3K1):​c.2845_2847delACA​(p.Thr949del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,571,420 control chromosomes in the GnomAD database, including 459,174 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45178 hom., cov: 0)
  • Exomes 𝑓: 0.77 (413996 hom.)
• Consequence: MAP3K1 NM_005921.2 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.28
• Publications: 23 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 -16 ACMG points.

• BP6: Variant 5-56882021-TCAA-T is Benign according to our data. Variant chr5-56882021-TCAA-T is described in ClinVar as Benign. ClinVar VariationId is 435819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.813 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.2845_2847delACA	p.Thr949del	conservative_inframe_deletion	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.2845_2847delACA	p.Thr949del	conservative_inframe_deletion	Exon 14 of 20	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.2839_2841delACA	p.Thr947del	conservative_inframe_deletion	Exon 14 of 20	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.2644_2646delACA	p.Thr882del	conservative_inframe_deletion	Exon 13 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes AF: 0.771 AC: 116272 AN: 150860 Hom.: 45126 Cov.: 0

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.767

Gnomad FIN AF: 0.805

Gnomad MID AF: 0.704

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.770

GnomAD2 exomes AF: 0.740 AC: 169887 AN: 229430 AF XY: 0.750

Gnomad AFR exome AF: 0.730

Gnomad AMR exome AF: 0.577

Gnomad ASJ exome AF: 0.806

Gnomad EAS exome AF: 0.551

Gnomad FIN exome AF: 0.791

Gnomad NFE exome AF: 0.805

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.770 AC: 1093464 AN: 1420440 Hom.: 413996 AF XY: 0.770 AC XY: 544151 AN XY: 707110

African (AFR) AF: 0.709 AC: 23240 AN: 32774

American (AMR) AF: 0.580 AC: 25545 AN: 44024

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 20185 AN: 25518

East Asian (EAS) AF: 0.553 AC: 21710 AN: 39240

South Asian (SAS) AF: 0.743 AC: 62721 AN: 84404

European-Finnish (FIN) AF: 0.778 AC: 40643 AN: 52228

Middle Eastern (MID) AF: 0.760 AC: 4300 AN: 5656

European-Non Finnish (NFE) AF: 0.789 AC: 850655 AN: 1077706

Other (OTH) AF: 0.755 AC: 44465 AN: 58890

GnomAD4 genome AF: 0.771 AC: 116380 AN: 150980 Hom.: 45178 Cov.: 0 AF XY: 0.765 AC XY: 56417 AN XY: 73700

African (AFR) AF: 0.742 AC: 30455 AN: 41030

American (AMR) AF: 0.671 AC: 10185 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2829 AN: 3462

East Asian (EAS) AF: 0.575 AC: 2937 AN: 5108

South Asian (SAS) AF: 0.767 AC: 3671 AN: 4786

European-Finnish (FIN) AF: 0.805 AC: 8380 AN: 10406

Middle Eastern (MID) AF: 0.709 AC: 207 AN: 292

European-Non Finnish (NFE) AF: 0.819 AC: 55461 AN: 67728

Other (OTH) AF: 0.771 AC: 1617 AN: 2098

Alfa AF: 0.760 Hom.: 4880

Bravo AF: 0.759

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=82/18	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: rs5868032; hg19: chr5-56177848; COSMIC: COSV68121469; COSMIC: COSV68121469;