Genetic Variant FOXP1:p.Val513Glu (chr3-70972669-A-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_001349338.3(FOXP1):c.1538T>A(p.Val513Glu) 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. 13/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V513A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

FOXP1
NM_001349338.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.32

Publications

0 publications found

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 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

FOXP1 links:

ENSG00000285708 (HGNC:):

ENSG00000285708 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr3-70972669-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 522138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3 link	c.1538T>A	p.Val513Glu	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 link	c.1538T>A	p.Val513Glu	missense_variant	Exon 18 of 21		NM_001349338.3	ENSP00000497369.1		Q9H334-1
ENSG00000285708	ENST00000647725.1 link	c.1538T>A	p.Val513Glu	missense_variant	Exon 23 of 26			ENSP00000497585.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

.;.;.;.;.;T;.;T;T;T;.;.;T;T;.;.;T;T;T;T;T;T;T;.

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.95

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

3.8

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

PhyloP100

9.3

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.0

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

REVEL

Pathogenic

0.98

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

0.93

MutPred

0.77

Gain of disorder (P = 0.0018);Gain of disorder (P = 0.0018);.;Gain of disorder (P = 0.0018);.;.;.;.;.;.;Gain of disorder (P = 0.0018);.;.;.;.;Gain of disorder (P = 0.0018);.;.;Gain of disorder (P = 0.0018);.;.;.;Gain of disorder (P = 0.0018);Gain of disorder (P = 0.0018);

MVP

0.98

MPC

4.6

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over