chr3-70972152-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001349338.3(FOXP1):c.1652+403A>G variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,532,252 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 69 hom. )

Consequence

FOXP1
NM_001349338.3 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.76

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009577841).

BP6

Variant 3-70972152-T-C is Benign according to our data. Variant chr3-70972152-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 376816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3 link	c.1652+403A>G		intron_variant	Intron 18 of 20	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3 link	c.1652+403A>G		intron_variant	Intron 18 of 20		NM_001349338.3	ENSP00000497369.1
ENSG00000285708	ENST00000647725.1 link	c.1652+403A>G		intron_variant	Intron 23 of 25			ENSP00000497585.1

Frequencies

GnomAD3 genomes

AF:

0.00348

AC:

530

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0395

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00580

AC:

761

AN:

131240

AF XY:

0.00553

show subpopulations

Gnomad AFR exome

AF:

0.000466

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.00235

Gnomad EAS exome

AF:

0.0366

Gnomad FIN exome

AF:

0.0108

Gnomad NFE exome

AF:

0.000231

Gnomad OTH exome

AF:

0.00595

GnomAD4 exome

AF:

0.00232

AC:

3201

AN:

1380020

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

1546

AN XY:

680786

show subpopulations

African (AFR)

AF:

0.000351

AC:

AN:

31348

American (AMR)

AF:

0.00979

AC:

340

AN:

34714

Ashkenazi Jewish (ASJ)

AF:

0.00168

AC:

AN:

24990

East Asian (EAS)

AF:

0.0561

AC:

2003

AN:

35716

South Asian (SAS)

AF:

0.000423

AC:

AN:

78070

European-Finnish (FIN)

AF:

0.0120

AC:

409

AN:

34016

Middle Eastern (MID)

AF:

0.000883

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.000155

AC:

167

AN:

1077748

Other (OTH)

AF:

0.00331

AC:

191

AN:

57756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

173

346

518

691

864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00349

AC:

532

AN:

152232

Hom.:

Cov.:

AF XY:

0.00429

AC XY:

319

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

41544

American (AMR)

AF:

0.00562

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.0398

AC:

206

AN:

5174

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0162

AC:

172

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68020

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00242

Hom.:

Bravo

AF:

0.00332

ExAC

AF:

0.00157

AC:

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 15, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FOXP1-related disorder

Benign:1

Aug 20, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0

.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;.

MetaRNN

Benign

0.0096

T;T

MutationAssessor

Benign

0.0

.;.

PhyloP100

7.8

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0010

D;.

Vest4

0.95

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

gMVP

0.92

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over