chr5-56838449-A-G

Variant names:

• chr5-56838449-A-G
• rs16886397
• NM_005921.2:c.483-18151A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_005921.2(MAP3K1):​c.483-18151A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 152,328 control chromosomes in the GnomAD database, including 286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.059 (286 hom., cov: 32)
• Consequence: MAP3K1 NM_005921.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.48
• 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, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 5-56838449-A-G is Benign according to our data. Variant chr5-56838449-A-G is described in ClinVar as Benign. ClinVar VariationId is 539066.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.112 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.483-18151A>G		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.483-18151A>G		intron	N/A	ENSP00000382423.3

Frequencies

GnomAD3 genomes AF: 0.0593 AC: 9020 AN: 152210 Hom.: 286 Cov.: 32

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0570

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0569

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0621

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

GnomAD4 genome AF: 0.0592 AC: 9021 AN: 152328 Hom.: 286 Cov.: 32 AF XY: 0.0596 AC XY: 4440 AN XY: 74488

African (AFR) AF: 0.0382 AC: 1586 AN: 41572

American (AMR) AF: 0.0569 AC: 871 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 211 AN: 3472

East Asian (EAS) AF: 0.119 AC: 620 AN: 5190

South Asian (SAS) AF: 0.0563 AC: 272 AN: 4830

European-Finnish (FIN) AF: 0.0741 AC: 786 AN: 10608

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0661 AC: 4497 AN: 68030

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

Alfa AF: 0.0646 Hom.: 573

Bravo AF: 0.0589

Asia WGS AF: 0.0740 AC: 257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 6 Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.90
PhyloP100		1.5
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: rs16886397; hg19: chr5-56134276;