Variant chr3-70977678-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001349338.3(FOXP1):c.1393A>G(p.Arg465Gly) variant causes a missense change. 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

FOXP1
NM_001349338.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.92

Variant links:

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]

FOXP1 links:

ENSG00000285708 (HGNC:):

ENSG00000285708 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

PP5

Variant 3-70977678-T-C is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP1	NM_001349338.3 link	c.1393A>G	p.Arg465Gly	missense_variant	16/21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3 link	c.1393A>G	p.Arg465Gly	missense_variant	16/21		NM_001349338.3	ENSP00000497369.1		Q9H334-1
ENSG00000285708	ENST00000647725.1 link	c.1393A>G	p.Arg465Gly	missense_variant	21/26			ENSP00000497585.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability-severe speech delay-mild dysmorphism syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Oct 30, 2014	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2014-10-30 and interpreted as Pathogenic. Variant was initially reported on 2013-03-05 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -
Pathogenic, criteria provided, single submitter	clinical testing;in vitro	Language and Genetics Department, Max Planck Institute for Psycholinguistics	Jan 01, 2015	- -

INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 16, 2024

- -

Intellectual disability

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Sep 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

.;D;.;.;.;.;D;.;.;D;D;D;.;.;D;D;.;.;D;D;D;D;D;D;D;D;.

M_CAP

Pathogenic

0.55

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

MutationAssessor

Pathogenic

4.0

H;H;H;.;H;.;.;.;H;.;.;.;H;.;.;.;.;H;.;.;H;.;.;.;.;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.2

D;.;D;D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.89

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

0.96

MutPred

0.68

Loss of solvent accessibility (P = 0.0023);Loss of solvent accessibility (P = 0.0023);Loss of solvent accessibility (P = 0.0023);.;Loss of solvent accessibility (P = 0.0023);.;.;.;Loss of solvent accessibility (P = 0.0023);.;.;.;Loss of solvent accessibility (P = 0.0023);.;.;.;.;Loss of solvent accessibility (P = 0.0023);.;.;Loss of solvent accessibility (P = 0.0023);.;.;.;.;Loss of solvent accessibility (P = 0.0023);Loss of solvent accessibility (P = 0.0023);

MVP

0.94

MPC

2.0

ClinPred

1.0

GERP RS

6.2

Varity_R

0.97

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over