rs143853590

chr5-56875191-G-Achr5-56875191-G-Cchr5-56875191-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005921.2(MAP3K1):c.1846G>A(p.Gly616Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000994 in 1,614,128 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: 4.21

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043625057).
• BS2: High AC in GnomAd at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K1	NM_005921.2	c.1846G>A	p.Gly616Arg	missense_variant	10/20	ENST00000399503.4
MAP3K1	XM_047417218.1	c.1846G>A	p.Gly616Arg	missense_variant	10/18
MAP3K1	XM_047417219.1	c.1435G>A	p.Gly479Arg	missense_variant	11/21
MAP3K1	XM_047417220.1	c.1435G>A	p.Gly479Arg	missense_variant	11/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K1	ENST00000399503.4	c.1846G>A	p.Gly616Arg	missense_variant	10/20	1	NM_005921.2	P1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000610 AC: 152 AN: 249150 Hom.: 0 AF XY: 0.000651 AC XY: 88 AN XY: 135160

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000928

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000956

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00102 AC: 1493 AN: 1461828 Hom.: 2 Cov.: 32 AF XY: 0.00101 AC XY: 734 AN XY: 727214

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74488

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.00117

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000507 AC: 2

ESP6500EA AF: 0.00120 AC: 10

ExAC AF: 0.000496 AC: 60

EpiCase AF: 0.000709

EpiControl AF: 0.000830

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

46,XY sex reversal 6 Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 15, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 10, 2010	- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Apr 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.014	D
Sift4G	Benign	0.40	T
Polyphen		0.026	B
Vest4		0.30
MutPred		0.085		Gain of methylation at G616 (P = 0.026);
MVP		0.95
MPC		0.30
ClinPred		0.015	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.25

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: rs143853590; hg19: chr5-56171018;