3-70955832-GCACACACACACA-GCACACACACACACACACA

Variant names:

• chr3-70955832-G-GCACACA
• rs143202281
• NM_001349338.3:c.*3409_*3414dupTGTGTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001349338.3(FOXP1):​c.*3409_*3414dupTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 221,474 control chromosomes in the GnomAD database, including 683 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.056 (680 hom., cov: 26)
  • Exomes 𝑓: 0.014 (3 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.373
• Publications: 3 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: Illumina, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3409_*3414dupTGTGTG		3_prime_UTR_variant	Exon 21 of 21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3	c.*3409_*3414dupTGTGTG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3409_*3414dupTGTGTG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8227 AN: 147108 Hom.: 678 Cov.: 26

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.0269

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.00147

Gnomad EAS AF: 0.00835

Gnomad SAS AF: 0.00322

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00167

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0137 AC: 1015 AN: 74272 Hom.: 3 Cov.: 0 AF XY: 0.0125 AC XY: 425 AN XY: 34114

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.177 AC: 666 AN: 3762

American (AMR) AF: 0.0214 AC: 49 AN: 2292

Ashkenazi Jewish (ASJ) AF: 0.00129 AC: 6 AN: 4646

East Asian (EAS) AF: 0.00309 AC: 34 AN: 11020

South Asian (SAS) AF: 0.00843 AC: 6 AN: 712

European-Finnish (FIN) AF: 0.00949 AC: 3 AN: 316

Middle Eastern (MID) AF: 0.0135 AC: 6 AN: 446

European-Non Finnish (NFE) AF: 0.00180 AC: 81 AN: 44944

Other (OTH) AF: 0.0267 AC: 164 AN: 6134

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0561 AC: 8254 AN: 147202 Hom.: 680 Cov.: 26 AF XY: 0.0540 AC XY: 3867 AN XY: 71586

African (AFR) AF: 0.187 AC: 7541 AN: 40348

American (AMR) AF: 0.0224 AC: 328 AN: 14652

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 5 AN: 3404

East Asian (EAS) AF: 0.00857 AC: 43 AN: 5016

South Asian (SAS) AF: 0.00302 AC: 14 AN: 4640

European-Finnish (FIN) AF: 0.0101 AC: 96 AN: 9552

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.00167 AC: 111 AN: 66364

Other (OTH) AF: 0.0435 AC: 89 AN: 2044

Alfa AF: 0.000345 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143202281; hg19: chr3-71004983;