chr3-70977678-T-C

Variant names:

• chr3-70977678-T-C
• rs869025202
• NM_001349338.3:c.1393A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.92
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability-severe speech delay-mild dysmorphism syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000285708 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_001349338.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-70977677-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 559905.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 217264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP1	NM_001349338.3	MANE Select	c.1393A>G	p.Arg465Gly	missense	Exon 16 of 21	NP_001336267.1
	FOXP1	NM_001244810.2		c.1393A>G	p.Arg465Gly	missense	Exon 16 of 21	NP_001231739.1
	FOXP1	NM_001244814.3		c.1393A>G	p.Arg465Gly	missense	Exon 12 of 17	NP_001231743.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP1	ENST00000649528.3	MANE Select	c.1393A>G	p.Arg465Gly	missense	Exon 16 of 21	ENSP00000497369.1
	FOXP1	ENST00000318789.11	TSL:1	c.1393A>G	p.Arg465Gly	missense	Exon 16 of 21	ENSP00000318902.5
	ENSG00000285708	ENST00000647725.1		c.1393A>G	p.Arg465Gly	missense	Exon 21 of 26	ENSP00000497585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability-severe speech delay-mild dysmorphism syndrome Pathogenic:2

Oct 30, 2014

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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.

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

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

Intellectual disability Pathogenic:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		4.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.68		Loss of solvent accessibility (P = 0.0023)
MVP		0.94
MPC		2.0
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.97
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869025202; hg19: chr3-71026829;