chr3-71046963-G-C

Position:

chr3-71046963-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001349338.3(FOXP1):c.643C>G(p.Pro215Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,614,070 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

FOXP1
NM_001349338.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 8.92

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:

ENSG00000285708 (HGNC:):

ENSG00000285708 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04472947).

BP6

Variant 3-71046963-G-C is Benign according to our data. Variant chr3-71046963-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 129109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00114 (173/152292) while in subpopulation AMR AF= 0.00216 (33/15302). AF 95% confidence interval is 0.00158. There are 1 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 173 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP1	NM_001349338.3 linkuse as main transcript	c.643C>G	p.Pro215Ala	missense_variant	10/21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3 linkuse as main transcript	c.643C>G	p.Pro215Ala	missense_variant	10/21		NM_001349338.3	ENSP00000497369.1		Q9H334-1
ENSG00000285708	ENST00000647725.1 linkuse as main transcript	c.643C>G	p.Pro215Ala	missense_variant	15/26			ENSP00000497585.1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00154

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000924

AC:

232

AN:

251026

Hom.:

AF XY:

0.000914

AC XY:

124

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00160

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00114

AC:

1672

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

826

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000842

Gnomad4 NFE exome

AF:

0.00139

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152292

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00154

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.00108

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00105

AC:

127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	FOXP1: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2020	This variant is associated with the following publications: (PMID: 19352412, 20848658, 20950788, 26647308) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 27, 2019

- -

FOXP1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

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

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.019

MetaRNN

Benign

0.045

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;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.3

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

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.1

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

REVEL

Benign

0.27

Sift

Benign

0.033

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

Sift4G

Benign

0.20

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

Polyphen

0.99

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

Vest4

0.59

MVP

0.34

MPC

1.2

ClinPred

0.056

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.51

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