rs147674680

Variant names:

• chr3-70970756-G-A
• rs147674680
• NM_001349338.3:c.1702C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-70970756-G-A
• chr3-70970756-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001349338.3(FOXP1):​c.1702C>T​(p.Pro568Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,613,832 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:2
• Conservation: PhyloP100: 2.58
• Publications: 6 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, ClinGen
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000285708 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009845763).
• BP6: Variant 3-70970756-G-A is Benign according to our data. Variant chr3-70970756-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 55847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00168 (256/152314) while in subpopulation AFR AF = 0.00582 (242/41552). AF 95% confidence interval is 0.00522. There are 0 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 256 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP1	NM_001349338.3	MANE Select	c.1702C>T	p.Pro568Ser	missense	Exon 19 of 21	NP_001336267.1	Q548T7
	FOXP1	NM_001244810.2		c.1750C>T	p.Pro584Ser	missense	Exon 19 of 21	NP_001231739.1	Q9H334-8
	FOXP1	NM_001244814.3		c.1702C>T	p.Pro568Ser	missense	Exon 15 of 17	NP_001231743.1	Q9H334-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP1	ENST00000649528.3	MANE Select	c.1702C>T	p.Pro568Ser	missense	Exon 19 of 21	ENSP00000497369.1	Q9H334-1
	FOXP1	ENST00000318789.11	TSL:1	c.1702C>T	p.Pro568Ser	missense	Exon 19 of 21	ENSP00000318902.5	Q9H334-1
	ENSG00000285708	ENST00000647725.1		c.1702C>T	p.Pro568Ser	missense	Exon 24 of 26	ENSP00000497585.1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000402 AC: 101 AN: 251490 AF XY: 0.000272

Gnomad AFR exome AF: 0.00541

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000170 AC: 249 AN: 1461518 Hom.: 1 Cov.: 29 AF XY: 0.000160 AC XY: 116 AN XY: 727072

African (AFR) AF: 0.00624 AC: 209 AN: 33472

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111678

Other (OTH) AF: 0.000315 AC: 19 AN: 60378

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74486

African (AFR) AF: 0.00582 AC: 242 AN: 41552

American (AMR) AF: 0.000653 AC: 10 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000740 Hom.: 0

Bravo AF: 0.00199

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	FOXP1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	-	Aortic valve atresia;C0344760:Mitral atresia disorder;C4551854:Hypoplastic left heart syndrome 1 (1)
-	-	-	Pulmonary atresia with ventricular septal defect;C3178805:Visceral heterotaxy;C3274516:Single Ventricle Defect;CN029142:Familial atrioventricular septal defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.033
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.76	N
PhyloP100		2.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.33
Sift	Benign	0.24	T
Sift4G	Benign	0.89	T
Polyphen		0.0010	B
Vest4		0.26
MVP		0.38
MPC		0.20
ClinPred		0.017	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.65
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs147674680; hg19: chr3-71019907;