rs45556841

chr5-56882016-C-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.2816C>G(p.Ser939Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,544,892 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (35 hom., cov: 31)
  • Exomes 𝑓: 0.020 (367 hom.)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.11

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 (MetaRNN=0.0024033189).
• BP6: Variant 5-56882016-C-G is Benign according to our data. Variant chr5-56882016-C-G is described in ClinVar as [Benign]. Clinvar id is 471692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-56882016-C-G is described in Lovd as [Benign]. Variant chr5-56882016-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.028 (2324/83092) while in subpopulation AMR AF= 0.0418 (401/9598). AF 95% confidence interval is 0.0389. There are 35 homozygotes in gnomad4. There are 1062 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2326 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K1	NM_005921.2	c.2816C>G	p.Ser939Cys	missense_variant	14/20	ENST00000399503.4
MAP3K1	XM_047417218.1	c.2816C>G	p.Ser939Cys	missense_variant	14/18
MAP3K1	XM_047417219.1	c.2405C>G	p.Ser802Cys	missense_variant	15/21
MAP3K1	XM_047417220.1	c.2405C>G	p.Ser802Cys	missense_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K1	ENST00000399503.4	c.2816C>G	p.Ser939Cys	missense_variant	14/20	1	NM_005921.2	P1

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 2326 AN: 83008 Hom.: 35 Cov.: 31

Gnomad AFR AF: 0.00799

Gnomad AMI AF: 0.00484

Gnomad AMR AF: 0.0420

Gnomad ASJ AF: 0.0866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0115

Gnomad FIN AF: 0.00585

Gnomad MID AF: 0.0327

Gnomad NFE AF: 0.0406

Gnomad OTH AF: 0.0421

GnomAD3 exomes AF: 0.0158 AC: 3907 AN: 247510 Hom.: 47 AF XY: 0.0160 AC XY: 2150 AN XY: 134448

Gnomad AFR exome AF: 0.00404

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0435

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00511

Gnomad FIN exome AF: 0.00331

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0202 AC: 29477 AN: 1461800 Hom.: 367 Cov.: 72 AF XY: 0.0196 AC XY: 14265 AN XY: 727196

Gnomad4 AFR exome AF: 0.00364

Gnomad4 AMR exome AF: 0.0189

Gnomad4 ASJ exome AF: 0.0475

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00585

Gnomad4 FIN exome AF: 0.00386

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0212

GnomAD4 genome AF: 0.0280 AC: 2324 AN: 83092 Hom.: 35 Cov.: 31 AF XY: 0.0262 AC XY: 1062 AN XY: 40532

Gnomad4 AFR AF: 0.00791

Gnomad4 AMR AF: 0.0418

Gnomad4 ASJ AF: 0.0866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.00585

Gnomad4 NFE AF: 0.0406

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0228 Hom.: 47

Bravo AF: 0.0165

ESP6500AA AF: 0.00525 AC: 20

ESP6500EA AF: 0.0231 AC: 191

ExAC AF: 0.0150 AC: 1816

EpiCase AF: 0.0255

EpiControl AF: 0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MAP3K1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

46,XY sex reversal 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.033
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.11	T
Polyphen		0.10	B
Vest4		0.065
MPC		0.23
ClinPred		0.018	T
GERP RS		3.9
Varity_R		0.13
gMVP		0.12

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: rs45556841; hg19: chr5-56177843; COSMIC: COSV68127595; COSMIC: COSV68127595;