12-2858783-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021953.4(FOXM1):​c.2147G>A​(p.Arg716His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,614,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

FOXM1
NM_021953.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0092689395).
BS2
High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXM1NM_021953.4 linkc.2147G>A p.Arg716His 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
FOXM1ENST00000359843.8 linkc.2147G>A p.Arg716His missense_variant Exon 9 of 9 1 NM_021953.4 ENSP00000352901.4 Q08050-1

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00385
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000223
AC:
56
AN:
251438
Hom.:
0
AF XY:
0.000228
AC XY:
31
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00261
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000725
AC:
106
AN:
1461888
Hom.:
0
Cov.:
30
AF XY:
0.0000674
AC XY:
49
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00204
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152328
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00386
Gnomad4 SAS
AF:
0.00103
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000202
Hom.:
0
Bravo
AF:
0.000132
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000222
AC:
27

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 27, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2261G>A (p.R754H) alteration is located in exon 10 (coding exon 9) of the FOXM1 gene. This alteration results from a G to A substitution at nucleotide position 2261, causing the arginine (R) at amino acid position 754 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.12
CADD
Benign
19
DANN
Benign
0.94
DEOGEN2
Benign
0.050
T;.;.;T
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.88
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.82
T;T;T;T
M_CAP
Benign
0.057
D
MetaRNN
Benign
0.0093
T;T;T;T
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Uncertain
2.2
.;.;.;M
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.8
.;N;N;N
REVEL
Benign
0.27
Sift
Benign
0.11
.;T;T;T
Sift4G
Benign
0.15
T;T;T;T
Polyphen
0.026, 0.022, 0.0060
.;B;B;B
Vest4
0.14
MVP
0.76
MPC
0.28
ClinPred
0.037
T
GERP RS
0.93
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.042
gMVP
0.28

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.

Other links and lift over

dbSNP: rs146806643; hg19: chr12-2967949; API