3-70976961-G-C

Position:

• chr3-70976961-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001349338.3(FOXP1):​c.1510C>G​(p.Arg504Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

FOXP1 (HGNC:3823): (forkhead box P1) This gene belongs to subfamily P of the forkhead box (FOX) transcription factor family. Forkhead box transcription factors play important roles in the regulation of tissue- and cell type-specific gene transcription during both development and adulthood. Forkhead box P1 protein contains both DNA-binding- and protein-protein binding-domains. This gene may act as a tumor suppressor as it is lost in several tumor types and maps to a chromosomal region (3p14.1) reported to contain a tumor suppressor gene(s). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ENSG00000285708 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.1510C>G	p.Arg504Gly	missense_variant	17/21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3	c.1510C>G	p.Arg504Gly	missense_variant	17/21		NM_001349338.3	ENSP00000497369.1
ENSG00000285708	ENST00000647725.1	c.1510C>G	p.Arg504Gly	missense_variant	22/26			ENSP00000497585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 26, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	.;T;.;.;.;.;T;.;.;T;T;T;.;.;T;T;.;.;T;T;T;T;D;T;T;T;.
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.2	L;L;L;.;L;.;.;.;L;.;.;.;L;.;.;.;.;L;.;.;L;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	D;.;D;D;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;.;.;.;D;.;.;.;.
REVEL	Pathogenic	0.73
Sift	Benign	0.042	D;.;D;D;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;.;.;.;D;.;.;.;.
Sift4G	Uncertain	0.015	D;D;D;D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.36	B;.;B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;B;.;.;B;.;.;.;.;.;.
Vest4		0.88
MutPred		0.40		Loss of stability (P = 0.0138);Loss of stability (P = 0.0138);Loss of stability (P = 0.0138);.;Loss of stability (P = 0.0138);.;.;.;Loss of stability (P = 0.0138);.;.;.;Loss of stability (P = 0.0138);.;.;.;.;Loss of stability (P = 0.0138);.;.;Loss of stability (P = 0.0138);.;.;.;.;Loss of stability (P = 0.0138);Loss of stability (P = 0.0138);
MVP		0.85
MPC		3.4
ClinPred		0.96	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.56
gMVP		0.86

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: rs797045585; hg19: chr3-71026112; COSMIC: COSV59550417;