chr5-56881916-G-A

Position:

• chr5-56881916-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005921.2(MAP3K1):​c.2716G>A​(p.Val906Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,613,750 control chromosomes in the GnomAD database, including 520,423 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 0.77 (45806 hom., cov: 30)
  • Exomes 𝑓: 0.80 (474617 hom.)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.45

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=7.638531E-7).
• BP6: Variant 5-56881916-G-A is Benign according to our data. Variant chr5-56881916-G-A is described in ClinVar as [Benign]. Clinvar id is 518365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-56881916-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K1	NM_005921.2	c.2716G>A	p.Val906Ile	missense_variant	14/20	ENST00000399503.4
MAP3K1	XM_047417218.1	c.2716G>A	p.Val906Ile	missense_variant	14/18
MAP3K1	XM_047417219.1	c.2305G>A	p.Val769Ile	missense_variant	15/21
MAP3K1	XM_047417220.1	c.2305G>A	p.Val769Ile	missense_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K1	ENST00000399503.4	c.2716G>A	p.Val906Ile	missense_variant	14/20	1	NM_005921.2	P1

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117429 AN: 151824 Hom.: 45752 Cov.: 30

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.712

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.819

Gnomad EAS AF: 0.578

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.774

GnomAD3 exomes AF: 0.758 AC: 188624 AN: 248982 Hom.: 72588 AF XY: 0.767 AC XY: 103576 AN XY: 135060

Gnomad AFR exome AF: 0.747

Gnomad AMR exome AF: 0.591

Gnomad ASJ exome AF: 0.821

Gnomad EAS exome AF: 0.567

Gnomad SAS exome AF: 0.775

Gnomad FIN exome AF: 0.806

Gnomad NFE exome AF: 0.820

Gnomad OTH exome AF: 0.771

GnomAD4 exome AF: 0.803 AC: 1174502 AN: 1461808 Hom.: 474617 Cov.: 60 AF XY: 0.803 AC XY: 583889 AN XY: 727192

Gnomad4 AFR exome AF: 0.739

Gnomad4 AMR exome AF: 0.600

Gnomad4 ASJ exome AF: 0.825

Gnomad4 EAS exome AF: 0.569

Gnomad4 SAS exome AF: 0.778

Gnomad4 FIN exome AF: 0.807

Gnomad4 NFE exome AF: 0.824

Gnomad4 OTH exome AF: 0.788

GnomAD4 genome AF: 0.774 AC: 117538 AN: 151942 Hom.: 45806 Cov.: 30 AF XY: 0.769 AC XY: 57084 AN XY: 74254

Gnomad4 AFR AF: 0.747

Gnomad4 AMR AF: 0.674

Gnomad4 ASJ AF: 0.819

Gnomad4 EAS AF: 0.579

Gnomad4 SAS AF: 0.769

Gnomad4 FIN AF: 0.809

Gnomad4 NFE AF: 0.821

Gnomad4 OTH AF: 0.776

Alfa AF: 0.802 Hom.: 125229

Bravo AF: 0.760

TwinsUK AF: 0.828 AC: 3072

ALSPAC AF: 0.826 AC: 3184

ESP6500AA AF: 0.745 AC: 2819

ESP6500EA AF: 0.823 AC: 6785

ExAC AF: 0.764 AC: 92324

Asia WGS AF: 0.697 AC: 2425 AN: 3478

EpiCase AF: 0.815

EpiControl AF: 0.817

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

46,XY sex reversal 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Nov 02, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.2
DANN	Benign	0.14
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.90
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.31	T
MetaRNN	Benign	7.6e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.11	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.080
Sift	Benign	0.85	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.19
ClinPred		0.0037	T
GERP RS		3.6
Varity_R		0.024
gMVP		0.092

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: rs832582; hg19: chr5-56177743; COSMIC: COSV68122270; COSMIC: COSV68122270;