12-2858880-G-C

Variant names:

• chr12-2858880-G-C
• rs2098099704
• NM_021953.4:c.2050C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021953.4(FOXM1):​c.2050C>G​(p.Leu684Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L684F) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: FOXM1 NM_021953.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.118688226).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXM1	NM_021953.4	MANE Select	c.2050C>G	p.Leu684Val	missense	Exon 9 of 9	NP_068772.2
	FOXM1	NM_001413925.1		c.2167C>G	p.Leu723Val	missense	Exon 10 of 10	NP_001400854.1
	FOXM1	NM_202002.3		c.2164C>G	p.Leu722Val	missense	Exon 10 of 10	NP_973731.1	Q08050-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXM1	ENST00000359843.8	TSL:1 MANE Select	c.2050C>G	p.Leu684Val	missense	Exon 9 of 9	ENSP00000352901.4	Q08050-1
	FOXM1	ENST00000342628.6	TSL:1	c.2164C>G	p.Leu722Val	missense	Exon 10 of 10	ENSP00000342307.2	Q08050-3
	FOXM1	ENST00000361953.7	TSL:1	c.2005C>G	p.Leu669Val	missense	Exon 8 of 8	ENSP00000354492.3	Q08050-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.015	D
Sift4G	Benign	0.17	T
Polyphen		0.96	D
Vest4		0.026
MutPred		0.15		Gain of catalytic residue at L682 (P = 0.009)
MVP		0.76
MPC		0.28
ClinPred		0.42	T
GERP RS		3.8
Varity_R		0.14
gMVP		0.090
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs2098099704; hg19: chr12-2968046;