chr3-71198369-A-G

Position:

chr3-71198369-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_001349338.3(FOXP1):c.13T>C(p.Ser5Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000784 in 1,389,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

FOXP1
NM_001349338.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 8.37

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.4137423).

BP6

Variant 3-71198369-A-G is Benign according to our data. Variant chr3-71198369-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211036.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000121 (16/132296) while in subpopulation NFE AF= 0.000217 (14/64408). AF 95% confidence interval is 0.000131. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP1	NM_001349338.3 linkuse as main transcript	c.13T>C	p.Ser5Pro	missense_variant	6/21	ENST00000649528.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP1	ENST00000649528.3 linkuse as main transcript	c.13T>C	p.Ser5Pro	missense_variant	6/21		NM_001349338.3	P4	Q9H334-1

Frequencies

GnomAD3 genomes

AF:

0.000121

AC:

AN:

132296

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000184

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000217

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

251072

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000740

AC:

AN:

1257424

Hom.:

Cov.:

AF XY:

0.0000882

AC XY:

AN XY:

623602

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000104

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.0000282

Gnomad4 NFE exome

AF:

0.0000796

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000121

AC:

AN:

132296

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

62496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000184

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000217

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000150

Hom.:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in individual with intellectual disability who inherited variant from parent; however, variant also seen in matched controls and clinical information not provided on parents (Horn et al., 2010); This variant is associated with the following publications: (PMID: 20848658) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	FOXP1: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 29, 2014

- -

FOXP1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2023

The FOXP1 c.13T>C variant is predicted to result in the amino acid substitution p.Ser5Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-71247520-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.;D;.;D;.;.;.;.;D;.;.;D;.;D;.;.;T;.;.;.;.;.;.;.;.;.;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.41

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.3

M;M;M;M;M;.;.;M;.;M;M;.;M;M;M;.;.;.;.;.;M;M;M;M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PROVEAN

Uncertain

-2.5

D;.;D;D;.;.;.;.;.;D;N;.;.;.;.;D;.;.;.;.;.;D;.;.;.;.;.;.;.

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0030

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

Polyphen

0.97

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

Vest4

0.68

MutPred

0.11

Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);Loss of phosphorylation at S5 (P = 0.018);

MVP

0.89

ClinPred

0.38

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.74

gMVP

0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over