3-70955832-GCACACACACACA-GCACACACACACACACACACACACA

Variant names:

• chr3-70955832-G-GCACACACACACA
• rs143202281
• NM_001349338.3:c.*3403_*3414dupTGTGTGTGTGTG

Variant summary

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

The NM_001349338.3(FOXP1):​c.*3403_*3414dupTGTGTGTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00838 in 221,482 control chromosomes in the GnomAD database, including 15 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0063 (15 hom., cov: 26)
  • Exomes 𝑓: 0.012 (0 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 (EAS) allele frequency at 95% confidence interval = 0.0833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3403_*3414dupTGTGTGTGTGTG		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.*3403_*3414dupTGTGTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3403_*3414dupTGTGTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.00630 AC: 927 AN: 147164 Hom.: 15 Cov.: 26

Gnomad AFR AF: 0.00730

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00219

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0901

Gnomad SAS AF: 0.00967

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00139

Gnomad OTH AF: 0.00395

GnomAD4 exome AF: 0.0125 AC: 925 AN: 74222 Hom.: 0 Cov.: 0 AF XY: 0.0125 AC XY: 427 AN XY: 34094

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

African (AFR) AF: 0.00525 AC: 20 AN: 3808

American (AMR) AF: 0.000873 AC: 2 AN: 2292

Ashkenazi Jewish (ASJ) AF: 0.000215 AC: 1 AN: 4646

East Asian (EAS) AF: 0.0723 AC: 791 AN: 10934

South Asian (SAS) AF: 0.00704 AC: 5 AN: 710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 316

Middle Eastern (MID) AF: 0.00224 AC: 1 AN: 446

European-Non Finnish (NFE) AF: 0.00145 AC: 65 AN: 44936

Other (OTH) AF: 0.00652 AC: 40 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: 0.00632 AC: 931 AN: 147260 Hom.: 15 Cov.: 26 AF XY: 0.00679 AC XY: 486 AN XY: 71620

African (AFR) AF: 0.00728 AC: 294 AN: 40406

American (AMR) AF: 0.00218 AC: 32 AN: 14652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.0901 AC: 452 AN: 5014

South Asian (SAS) AF: 0.0106 AC: 49 AN: 4640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9552

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

European-Non Finnish (NFE) AF: 0.00139 AC: 92 AN: 66364

Other (OTH) AF: 0.00440 AC: 9 AN: 2046

Alfa AF: 0.00 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

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;