rs140161845

chr3-70970749-T-Cchr3-70970749-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001349338.3(FOXP1):c.1709A>G(p.Asn570Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,470 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.972

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 5 uncertain in NM_001349338.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.016649753).
• BP6: Variant 3-70970749-T-C is Benign according to our data. Variant chr3-70970749-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 211041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-70970749-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00135 (205/152186) while in subpopulation NFE AF= 0.00253 (172/68024). AF 95% confidence interval is 0.00222. There are 1 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 205 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP1	NM_001349338.3	c.1709A>G	p.Asn570Ser	missense_variant	19/21	ENST00000649528.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP1	ENST00000649528.3	c.1709A>G	p.Asn570Ser	missense_variant	19/21		NM_001349338.3	P4

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00147 AC: 369 AN: 251494 Hom.: 0 AF XY: 0.00151 AC XY: 205 AN XY: 135922

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00240 AC: 3508 AN: 1461284 Hom.: 6 Cov.: 29 AF XY: 0.00229 AC XY: 1662 AN XY: 726994

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00298

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152186 Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74360

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00211 Hom.: 0

Bravo AF: 0.00131

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00154 AC: 187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Jun 02, 2017	BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 24, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 05, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	FOXP1: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	This variant is associated with the following publications: (PMID: 20848658, 26647308, 20950788) -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 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. -

FOXP1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.;T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;T;.;.;T;.;.;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.017	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	-0.40	T
MutationAssessor	Benign	-0.28	N;.;N;.;N;.;.;.;.;.;.;.;N;.;.;.;.;N;.;.;N;.;.;.;.;.
MutationTaster	Benign	0.98	D;D;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N;.;N;N;.;.;.;.;.;.;.;.;N;.;N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.11	T;.;T;T;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.29	T;T;T;T;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0	B;.;B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;B;.;.;B;.;.;.;.;.
Vest4		0.22
MVP		0.53
MPC		0.15
ClinPred		0.023	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs140161845; hg19: chr3-71019900;