3-70977677-C-G

Position:

• chr3-70977677-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001349338.3(FOXP1):​c.1394G>C​(p.Arg465Thr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-70977678-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 3-70977677-C-G is Pathogenic according to our data. Variant chr3-70977677-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 559905.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP1	NM_001349338.3	c.1394G>C	p.Arg465Thr	missense_variant	16/21	ENST00000649528.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP1	ENST00000649528.3	c.1394G>C	p.Arg465Thr	missense_variant	16/21		NM_001349338.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability-severe speech delay-mild dysmorphism syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Nov 10, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;D;D;D;.;.;D;D;.;.;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.91	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	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H;.;H;.;.;.;H;.;.;.;H;.;.;.;.;H;.;.;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	D;.;D;D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;D;D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.;.
Vest4		0.95
MutPred		0.64		Loss of solvent accessibility (P = 0.008);Loss of solvent accessibility (P = 0.008);Loss of solvent accessibility (P = 0.008);.;Loss of solvent accessibility (P = 0.008);.;.;.;Loss of solvent accessibility (P = 0.008);.;.;.;Loss of solvent accessibility (P = 0.008);.;.;.;.;Loss of solvent accessibility (P = 0.008);.;.;Loss of solvent accessibility (P = 0.008);.;.;.;.;Loss of solvent accessibility (P = 0.008);Loss of solvent accessibility (P = 0.008);
MVP		0.92
MPC		2.1
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1553668196; hg19: chr3-71026828; COSMIC: COSV100561305;