5-56880818-T-G

Variant names:

• chr5-56880818-T-G
• rs201491763
• NM_005921.2:c.2179+16T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005921.2(MAP3K1):​c.2179+16T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,581,146 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (24 hom.)
• Consequence: MAP3K1 NM_005921.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.191
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 5-56880818-T-G is Benign according to our data. Variant chr5-56880818-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 530 AD gene.

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.2179+16T>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.2179+16T>G		intron	N/A	ENSP00000382423.3

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 530 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00575

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00318 AC: 788 AN: 247550 AF XY: 0.00330

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.000932

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00516 AC: 7367 AN: 1428882 Hom.: 24 Cov.: 26 AF XY: 0.00510 AC XY: 3635 AN XY: 712998

African (AFR) AF: 0.000883 AC: 29 AN: 32852

American (AMR) AF: 0.00166 AC: 74 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00217 AC: 56 AN: 25862

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39484

South Asian (SAS) AF: 0.00309 AC: 264 AN: 85482

European-Finnish (FIN) AF: 0.000769 AC: 41 AN: 53310

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5680

European-Non Finnish (NFE) AF: 0.00614 AC: 6649 AN: 1082366

Other (OTH) AF: 0.00422 AC: 250 AN: 59272

GnomAD4 genome AF: 0.00348 AC: 530 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74454

African (AFR) AF: 0.000890 AC: 37 AN: 41566

American (AMR) AF: 0.00157 AC: 24 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00575 AC: 391 AN: 68012

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00367

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

46,XY sex reversal 6 Benign:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

May 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely 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	-0.71
CADD	Benign	6.6
DANN	Benign	0.74
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism

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: rs201491763; hg19: chr5-56176645;