3-70972633-C-T

Position:

• chr3-70972633-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001349338.3(FOXP1):​c.1574G>A​(p.Arg525Gln) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• 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]

ENSG00000285708 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 3-70972633-C-T is Pathogenic according to our data. Variant chr3-70972633-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-70972633-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.1574G>A	p.Arg525Gln	missense_variant	18/21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3	c.1574G>A	p.Arg525Gln	missense_variant	18/21		NM_001349338.3	ENSP00000497369.1
ENSG00000285708	ENST00000647725.1	c.1574G>A	p.Arg525Gln	missense_variant	23/26			ENSP00000497585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FOXP1: PM6:Strong, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2021	Published functional studies suggest a damaging effect (loss of DNA-binding ability) (Johnson et al., 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25326635, 28884888, 27657687, 30385778) -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 12, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FOXP1 function (PMID: 30385778). 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. ClinVar contains an entry for this variant (Variation ID: 521111). This missense change has been observed in individual(s) with clinical features of FOXP1-related conditions (PMID: 27657687, 30385778). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 525 of the FOXP1 protein (p.Arg525Gln). -

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

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Aug 04, 2022	This sequence change in FOXP1 is predicted to replace arginine with glutamine at codon 525, p.(Arg525Gln). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in Fork-head DNA-binding domain a region, amino acids 465-555, that is defined as a mutational hotspot and critical functional domain (PMID: 31199603). There is a small physicochemical difference between arginine and glutamine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual and as a de novo occurrence with unconfirmed parental relationships in two individuals with syndromic intellectual disability (PMID: 27657687, 30385778; DECIPHER). This variant has also been reported in an additional four probands with unknown/unconfirmed de novo status and consistent phenotypes resembling FOXP1 syndrome (PMID: 30385778, 34588003; ClinVar: SCV000741551.2, SCV001905601.1). A luciferase assay in HEK293 cells showed diminished transcriptional repression indicating that this variant impacts protein function (PMID: 30385778). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS2/PM6_Strong, PM1, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2020	Variant summary: FOXP1 c.1574G>A (p.Arg525Gln) results in a conservative amino acid change located in the Fork Head domain (IPR001766) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. c.1574G>A has been reported in the literature in three patients who all presented with global developmental delay, autism spectrum disorder, and characteristic dysmorphic features, with other phenotypic features being unique to particular patients (Bekheirnia_2017, Myers_2017, Johnson_2018). Two of these patients had confirmed de novo inheritance of the variant, while one was missing maternal sample, however paternal and unaffected full siblings samples were negative for the variant. A functional study reported that despite normal nuclear localization of the variant protein in vitro, the ability to transcriptionally repress the SV40 promoter was severely diminished compared to wild-type (Johnson_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder with language impairment with or without autistic features (MIM#613670). Dominant-negative is also a suggested disease mechanism (OMIM). (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 glutamine. (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) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the forkhead domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed as de novo in at least two individuals with FOXP1-related conditions (PMID: 30385778). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;.;D;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;.;.;.;D;.;D;D;D;.;.;D;D;.;.;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.84	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	3.1	M;M;.;M;.;.;.;.;.;.;M;.;.;.;.;M;.;.;M;.;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.2	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;.;D;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.91
MutPred		0.60		Loss of MoRF binding (P = 0.014);Loss of MoRF binding (P = 0.014);.;Loss of MoRF binding (P = 0.014);.;.;.;.;.;.;Loss of MoRF binding (P = 0.014);.;.;.;.;Loss of MoRF binding (P = 0.014);.;.;Loss of MoRF binding (P = 0.014);.;.;.;Loss of MoRF binding (P = 0.014);Loss of MoRF binding (P = 0.014);
MVP		0.96
MPC		3.1
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553663084; hg19: chr3-71021784; COSMIC: COSV59557791;