5-56876951-G-A

Variant names:

• chr5-56876951-G-A
• rs2548663
• NM_005921.2:c.1965+1641G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005921.2(MAP3K1):​c.1965+1641G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 151,982 control chromosomes in the GnomAD database, including 33,330 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.65 (33330 hom., cov: 31)
• Consequence: MAP3K1 NM_005921.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.711 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.1965+1641G>A		intron	N/A	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.1965+1641G>A		intron	N/A	ENSP00000382423.3	Q13233
	MAP3K1	ENST00000872825.1		c.1959+1641G>A		intron	N/A	ENSP00000542884.1
	MAP3K1	ENST00000948659.1		c.1764+1641G>A		intron	N/A	ENSP00000618718.1

Frequencies

GnomAD3 genomes AF: 0.653 AC: 99213 AN: 151866 Hom.: 33301 Cov.: 31

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.661

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.653 AC: 99281 AN: 151982 Hom.: 33330 Cov.: 31 AF XY: 0.644 AC XY: 47826 AN XY: 74302

African (AFR) AF: 0.651 AC: 26978 AN: 41428

American (AMR) AF: 0.515 AC: 7864 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 2502 AN: 3468

East Asian (EAS) AF: 0.232 AC: 1197 AN: 5160

South Asian (SAS) AF: 0.482 AC: 2320 AN: 4816

European-Finnish (FIN) AF: 0.721 AC: 7629 AN: 10584

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48662 AN: 67946

Other (OTH) AF: 0.656 AC: 1383 AN: 2108

Alfa AF: 0.697 Hom.: 16481

Bravo AF: 0.638

Asia WGS AF: 0.387 AC: 1348 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.91
PhyloP100		0.28
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: rs2548663; hg19: chr5-56172778;