chr5-56850170-G-A

Variant names:

• chr5-56850170-G-A
• rs33330
• NM_005921.2:c.483-6430G>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.483-6430G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 152,120 control chromosomes in the GnomAD database, including 5,630 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 0.24 (5630 hom., cov: 32)
• Consequence: MAP3K1 NM_005921.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.537
• Publications: 14 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

ENSG00000237705 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.346 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	NM_005921.2	MANE Select	c.483-6430G>A		intron	N/A	NP_005912.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.483-6430G>A		intron	N/A	ENSP00000382423.3
	ENSG00000237705	ENST00000415589.1	TSL:3	n.421+1820C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.237 AC: 35974 AN: 152002 Hom.: 5632 Cov.: 32

Gnomad AFR AF: 0.0683

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.00965

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.282

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

GnomAD4 genome AF: 0.236 AC: 35957 AN: 152120 Hom.: 5630 Cov.: 32 AF XY: 0.228 AC XY: 16934 AN XY: 74380

African (AFR) AF: 0.0682 AC: 2830 AN: 41514

American (AMR) AF: 0.217 AC: 3322 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1398 AN: 3472

East Asian (EAS) AF: 0.00967 AC: 50 AN: 5172

South Asian (SAS) AF: 0.133 AC: 641 AN: 4822

European-Finnish (FIN) AF: 0.275 AC: 2906 AN: 10562

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23798 AN: 67960

Other (OTH) AF: 0.277 AC: 586 AN: 2112

Alfa AF: 0.311 Hom.: 34096

Bravo AF: 0.226

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.3
DANN	Benign	0.28
PhyloP100		0.54
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: rs33330; hg19: chr5-56145997; COSMIC: COSV68122627;