3-70977677-C-T

Variant names:

• chr3-70977677-C-T
• rs1553668196
• NM_001349338.3:c.1394G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_001349338.3(FOXP1):​c.1394G>A​(p.Arg465Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 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: Likely_pathogenic. The variant received 7 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 chr3-70977678-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

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.1394G>A	p.Arg465Lys	missense	Exon 16 of 21	NP_001336267.1
	FOXP1	NM_001244810.2		c.1394G>A	p.Arg465Lys	missense	Exon 16 of 21	NP_001231739.1
	FOXP1	NM_001244814.3		c.1394G>A	p.Arg465Lys	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.1394G>A	p.Arg465Lys	missense	Exon 16 of 21	ENSP00000497369.1
	FOXP1	ENST00000318789.11	TSL:1	c.1394G>A	p.Arg465Lys	missense	Exon 16 of 21	ENSP00000318902.5
	ENSG00000285708	ENST00000647725.1		c.1394G>A	p.Arg465Lys	missense	Exon 21 of 26	ENSP00000497585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461782 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 465 of the FOXP1 protein (p.Arg465Lys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg465 amino acid residue in FOXP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26647308, 34588003). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with FOXP1-related conditions. This variant is not present in population databases (gnomAD no frequency).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	1.0	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.045	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.61		Gain of methylation at R465 (P = 0.004)
MVP		0.86
MPC		1.7
ClinPred		0.97	D
GERP RS		6.2
Varity_R		0.86
gMVP		0.93
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs1553668196; hg19: chr3-71026828;