NM_021953.4:c.1799C>T

Variant names:

• chr12-2859131-G-A
• rs369897716
• NM_021953.4:c.1799C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_021953.4(FOXM1):​c.1799C>T​(p.Thr600Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,605,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: FOXM1 NM_021953.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.23
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 23 AD gene.

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.1799C>T	p.Thr600Ile	missense	Exon 9 of 9	NP_068772.2
	FOXM1	NM_001413925.1		c.1916C>T	p.Thr639Ile	missense	Exon 10 of 10	NP_001400854.1
	FOXM1	NM_202002.3		c.1913C>T	p.Thr638Ile	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.1799C>T	p.Thr600Ile	missense	Exon 9 of 9	ENSP00000352901.4	Q08050-1
	FOXM1	ENST00000342628.6	TSL:1	c.1913C>T	p.Thr638Ile	missense	Exon 10 of 10	ENSP00000342307.2	Q08050-3
	FOXM1	ENST00000361953.7	TSL:1	c.1754C>T	p.Thr585Ile	missense	Exon 8 of 8	ENSP00000354492.3	Q08050-2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00144

GnomAD2 exomes AF: 0.0000330 AC: 8 AN: 242748 AF XY: 0.0000151

Gnomad AFR exome AF: 0.000402

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1453356 Hom.: 0 Cov.: 33 AF XY: 0.0000166 AC XY: 12 AN XY: 722160

African (AFR) AF: 0.000660 AC: 22 AN: 33328

American (AMR) AF: 0.0000450 AC: 2 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49690

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5734

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108458

Other (OTH) AF: 0.0000666 AC: 4 AN: 60084

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74382

African (AFR) AF: 0.000458 AC: 19 AN: 41512

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000495 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.87
MPC		0.82
ClinPred		0.91	D
GERP RS		4.6
Varity_R		0.63
gMVP		0.49
Mutation Taster		=67/33	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: rs369897716; hg19: chr12-2968297;