5-56880818-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 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

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]

ACMG classification

Verdict is Benign. Variant got -20 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 [Likely_benign]. Clinvar id is 445450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00348 (530/152264) while in subpopulation NFE AF= 0.00575 (391/68012). AF 95% confidence interval is 0.00528. There are 1 homozygotes in gnomad4. There are 229 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 530 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K1	NM_005921.2	c.2179+16T>G		intron_variant		ENST00000399503.4
MAP3K1	XM_047417218.1	c.2179+16T>G		intron_variant
MAP3K1	XM_047417219.1	c.1768+16T>G		intron_variant
MAP3K1	XM_047417220.1	c.1768+16T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K1	ENST00000399503.4	c.2179+16T>G		intron_variant		1	NM_005921.2	P1

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

GnomAD3 exomes AF: 0.00318 AC: 788 AN: 247550 Hom.: 5 AF XY: 0.00330 AC XY: 443 AN XY: 134264

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 SAS exome AF: 0.00276

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

Gnomad4 AFR exome AF: 0.000883

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00217

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00309

Gnomad4 FIN exome AF: 0.000769

Gnomad4 NFE exome AF: 0.00614

Gnomad4 OTH exome AF: 0.00422

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

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00575

Gnomad4 OTH AF: 0.00379

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	6.6
Dann	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs201491763; hg19: chr5-56176645; COSMIC: COSV104704818;