rs869025203

Variant names:

• chr3-70972667-G-A
• rs869025203
• NM_001349338.3:c.1540C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-70972667-G-A
• chr3-70972667-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001349338.3(FOXP1):​c.1540C>T​(p.Arg514Cys) 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. 13/20 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. R514H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• 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 Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-70972666-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 3-70972667-G-A is Pathogenic according to our data. Variant chr3-70972667-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-70972667-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.1540C>T	p.Arg514Cys	missense_variant	Exon 18 of 21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3	c.1540C>T	p.Arg514Cys	missense_variant	Exon 18 of 21		NM_001349338.3	ENSP00000497369.1
ENSG00000285708	ENST00000647725.1	c.1540C>T	p.Arg514Cys	missense_variant	Exon 23 of 26			ENSP00000497585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Jan 12, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26647308, 31199603, 28741757, 34109629, 31981491) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 514 of the FOXP1 protein (p.Arg514Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability syndrome (PMID: 26647308). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217265). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FOXP1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg514 amino acid residue in FOXP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28741757). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 29, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2, PM6, PS4_Moderate -

Intellectual disability-severe speech delay-mild dysmorphism syndrome Pathogenic:4

Jan 01, 2015

Language and Genetics Department, Max Planck Institute for Psycholinguistics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

- -

Nov 02, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with intellectual disability with language impairment and with or without autistic features (MIM#613670). Loss of function leading to haploinsufficiency has been demonstrated, however some variants have also been shown to bind to wild type FOXP1 and affect wild type function and localisation (PMID: 26647308). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional forkhead domain. Moreover, the affected residue is a DNA binding site (Decipher; NCBI conserved domain). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg514His) variant is de novo in three unrelated individuals with mild to severe intellectual disability (PMID: 28741757). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is de novo in two individuals with intellectual disability (ClinVar, PMID: 26647308). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs transfected into HEK293T cells resulted in reduced protein expression with subsequent mis-localisation and reduced transcriptional repression ability of the protein (PMID: 26647308). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1540C>T;p.(Arg514Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 217265; PMID: 26647308) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (Forkhead domain) - PM1. This variant is not present in population databases (rs869025203, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (PMID: 28741757 - c.1541G>A (p.Arg514His) - ) - .PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

FOXP1-related disorder Pathogenic:1

Jan 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FOXP1 c.1540C>T variant is predicted to result in the amino acid substitution p.Arg514Cys. This variant has been reported de novo in individuals with global developmental disorder, intellectual disability, and/or speech and language delay (Sollis et al. 2015. PubMed ID: 26647308; Braden et al. 2021. PubMed ID: 34109629). Function studies have shown that this variant impacts protein function (Sollis et al. 2015. PubMed ID: 26647308; Estruch et al. 2018. PMID: 29365100). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is interpreted as pathogenic in ClinVar by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/217265/). This variant is interpreted as pathogenic. -

INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES Pathogenic:1

Oct 16, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D;.;D;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;.;.;.;D;.;D;D;D;.;.;D;D;.;.;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.97	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	1.0	D
MutationAssessor	Pathogenic	4.0	H;H;.;H;.;.;.;.;.;.;H;.;.;.;.;H;.;.;H;.;.;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.5	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;.;D;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.94
MutPred		0.85		Loss of MoRF binding (P = 0.001);Loss of MoRF binding (P = 0.001);.;Loss of MoRF binding (P = 0.001);.;.;.;.;.;.;Loss of MoRF binding (P = 0.001);.;.;.;.;Loss of MoRF binding (P = 0.001);.;.;Loss of MoRF binding (P = 0.001);.;.;.;Loss of MoRF binding (P = 0.001);Loss of MoRF binding (P = 0.001);
MVP		0.99
MPC		4.1
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs869025203; hg19: chr3-71021818; COSMIC: COSV59538312;