12-2858924-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021953.4(FOXM1):c.2006C>G(p.Pro669Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00304 in 1,613,808 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P669H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 41 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 41 hom. )

Consequence

FOXM1
NM_021953.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.74

Variant links:

Genes affected

FOXM1 (HGNC:3818): (forkhead box M1) The protein encoded by this gene is a transcriptional activator involved in cell proliferation. The encoded protein is phosphorylated in M phase and regulates the expression of several cell cycle genes, such as cyclin B1 and cyclin D1. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

FOXM1 links:

ITFG2 (HGNC:30879): (integrin alpha FG-GAP repeat containing 2) Involved in cellular response to amino acid starvation; cellular response to glucose starvation; and negative regulation of TORC1 signaling. Located in lysosomal membrane. Part of KICSTOR complex. [provided by Alliance of Genome Resources, Apr 2022]

ITFG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038274825).

BP6

Variant 12-2858924-G-C is Benign according to our data. Variant chr12-2858924-G-C is described in ClinVar as [Benign]. Clinvar id is 711070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2030/152196) while in subpopulation AFR AF= 0.0455 (1888/41532). AF 95% confidence interval is 0.0438. There are 41 homozygotes in gnomad4. There are 958 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2030 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXM1	NM_021953.4 link	c.2006C>G	p.Pro669Arg	missense_variant	Exon 9 of 9	ENST00000359843.8	NP_068772.2	Q08050-1Q53Y49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXM1	ENST00000359843.8 link	c.2006C>G	p.Pro669Arg	missense_variant	Exon 9 of 9	1	NM_021953.4	ENSP00000352901.4		Q08050-1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2026

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0455

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00312

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00862

GnomAD3 exomes

AF:

0.00428

AC:

1072

AN:

250588

Hom.:

AF XY:

0.00365

AC XY:

494

AN XY:

135502

show subpopulations

Gnomad AFR exome

AF:

0.0477

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00448

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00372

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.000300

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00197

AC:

2877

AN:

1461612

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

1322

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.0495

Gnomad4 AMR exome

AF:

0.00262

Gnomad4 ASJ exome

AF:

0.00394

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.00329

Gnomad4 FIN exome

AF:

0.0000564

Gnomad4 NFE exome

AF:

0.000414

Gnomad4 OTH exome

AF:

0.00371

GnomAD4 genome

AF:

0.0133

AC:

2030

AN:

152196

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

958

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0455

Gnomad4 AMR

AF:

0.00445

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00312

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00853

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.0151

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0477

AC:

210

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00492

AC:

597

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.038

T;.;.;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.43

T;T;T;T

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.69

.;.;.;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.81

.;N;N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.011

.;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.21, 0.83, 0.74

.;B;P;P

Vest4

0.12

MVP

0.44

MPC

0.23

ClinPred

0.029

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.045

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over