3-70955832-GCACACACACACA-GCACACACACACACACACACACACACA

Variant names:

• chr3-70955832-G-GCACACACACACACA
• rs143202281
• NM_001349338.3:c.*3401_*3414dupTGTGTGTGTGTGTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001349338.3(FOXP1):​c.*3401_*3414dupTGTGTGTGTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 221,608 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00078 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0010 (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.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000781 (115/147264) while in subpopulation EAS AF = 0.00279 (14/5016). AF 95% confidence interval is 0.00169. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3401_*3414dupTGTGTGTGTGTGTG		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.*3401_*3414dupTGTGTGTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3401_*3414dupTGTGTGTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 114 AN: 147168 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000752

Gnomad ASJ AF: 0.00206

Gnomad EAS AF: 0.00278

Gnomad SAS AF: 0.00129

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000753

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00105 AC: 78 AN: 74344 Hom.: 0 Cov.: 0 AF XY: 0.000966 AC XY: 33 AN XY: 34146

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

African (AFR) AF: 0.00262 AC: 10 AN: 3810

American (AMR) AF: 0.00218 AC: 5 AN: 2290

Ashkenazi Jewish (ASJ) AF: 0.000861 AC: 4 AN: 4646

East Asian (EAS) AF: 0.00444 AC: 49 AN: 11026

South Asian (SAS) AF: 0.00421 AC: 3 AN: 712

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 446

European-Non Finnish (NFE) AF: 0.0000667 AC: 3 AN: 44954

Other (OTH) AF: 0.000651 AC: 4 AN: 6144

⚠️ 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: 0.000781 AC: 115 AN: 147264 Hom.: 0 Cov.: 26 AF XY: 0.000810 AC XY: 58 AN XY: 71620

African (AFR) AF: 0.00178 AC: 72 AN: 40408

American (AMR) AF: 0.000751 AC: 11 AN: 14652

Ashkenazi Jewish (ASJ) AF: 0.00206 AC: 7 AN: 3404

East Asian (EAS) AF: 0.00279 AC: 14 AN: 5016

South Asian (SAS) AF: 0.00129 AC: 6 AN: 4640

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000753 AC: 5 AN: 66364

Other (OTH) AF: 0.00 AC: 0 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

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;