3-70955832-GCACACACACACA-GCACACACACACACACACACACA

Variant names:

• chr3-70955832-G-GCACACACACA
• rs143202281
• NM_001349338.3:c.*3405_*3414dupTGTGTGTGTG

Variant summary

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

The NM_001349338.3(FOXP1):​c.*3405_*3414dupTGTGTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 221,092 control chromosomes in the GnomAD database, including 512 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.067 (508 hom., cov: 26)
  • Exomes 𝑓: 0.056 (4 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 = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3405_*3414dupTGTGTGTGTG		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.*3405_*3414dupTGTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3405_*3414dupTGTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.0669 AC: 9834 AN: 147082 Hom.: 506 Cov.: 26

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.0782

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.0385

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0711

GnomAD4 exome AF: 0.0557 AC: 4118 AN: 73914 Hom.: 4 Cov.: 0 AF XY: 0.0550 AC XY: 1868 AN XY: 33944

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

African (AFR) AF: 0.118 AC: 445 AN: 3776

American (AMR) AF: 0.0733 AC: 166 AN: 2266

Ashkenazi Jewish (ASJ) AF: 0.0425 AC: 196 AN: 4612

East Asian (EAS) AF: 0.183 AC: 1990 AN: 10884

South Asian (SAS) AF: 0.0696 AC: 49 AN: 704

European-Finnish (FIN) AF: 0.0160 AC: 5 AN: 312

Middle Eastern (MID) AF: 0.0541 AC: 24 AN: 444

European-Non Finnish (NFE) AF: 0.0217 AC: 971 AN: 44812

Other (OTH) AF: 0.0446 AC: 272 AN: 6104

⚠️ 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: 0.0669 AC: 9847 AN: 147178 Hom.: 508 Cov.: 26 AF XY: 0.0685 AC XY: 4903 AN XY: 71574

African (AFR) AF: 0.135 AC: 5441 AN: 40366

American (AMR) AF: 0.0705 AC: 1032 AN: 14640

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 137 AN: 3402

East Asian (EAS) AF: 0.148 AC: 744 AN: 5016

South Asian (SAS) AF: 0.0787 AC: 365 AN: 4640

European-Finnish (FIN) AF: 0.0563 AC: 537 AN: 9532

Middle Eastern (MID) AF: 0.0414 AC: 12 AN: 290

European-Non Finnish (NFE) AF: 0.0216 AC: 1432 AN: 66354

Other (OTH) AF: 0.0718 AC: 147 AN: 2046

Alfa AF: 0.00572 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;