3-70955832-G-GCACACACA

Variant names:

• chr3-70955832-G-GCACACACA
• rs143202281
• NM_001349338.3:c.*3407_*3414dupTGTGTGTG

Variant summary

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

The NM_001349338.3(FOXP1):​c.*3407_*3414dupTGTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 221,220 control chromosomes in the GnomAD database, including 126 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.024 (126 hom., cov: 26)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 = 0.0709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3407_*3414dupTGTGTGTG		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.*3407_*3414dupTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3407_*3414dupTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3594 AN: 147114 Hom.: 126 Cov.: 26

Gnomad AFR AF: 0.0731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00813

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.0756

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.000314

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000814

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.0136 AC: 1003 AN: 74010 Hom.: 0 Cov.: 0 AF XY: 0.0126 AC XY: 429 AN XY: 34000

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

African (AFR) AF: 0.0764 AC: 287 AN: 3758

American (AMR) AF: 0.0114 AC: 26 AN: 2284

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 8 AN: 4634

East Asian (EAS) AF: 0.0512 AC: 554 AN: 10822

South Asian (SAS) AF: 0.0126 AC: 9 AN: 712

European-Finnish (FIN) AF: 0.00633 AC: 2 AN: 316

Middle Eastern (MID) AF: 0.00676 AC: 3 AN: 444

European-Non Finnish (NFE) AF: 0.000935 AC: 42 AN: 44924

Other (OTH) AF: 0.0118 AC: 72 AN: 6116

⚠️ 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: 0.0245 AC: 3601 AN: 147210 Hom.: 126 Cov.: 26 AF XY: 0.0242 AC XY: 1735 AN XY: 71594

African (AFR) AF: 0.0731 AC: 2950 AN: 40368

American (AMR) AF: 0.00812 AC: 119 AN: 14648

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3404

East Asian (EAS) AF: 0.0754 AC: 378 AN: 5012

South Asian (SAS) AF: 0.0131 AC: 61 AN: 4640

European-Finnish (FIN) AF: 0.000314 AC: 3 AN: 9548

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.000814 AC: 54 AN: 66364

Other (OTH) AF: 0.0147 AC: 30 AN: 2044

Alfa AF: 0.00 Hom.: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual Disability with Language Impairment and Autistic Features Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;