3-70955832-GCACACACACACA-GCACACACACACACA

Variant names:

• chr3-70955832-G-GCA
• rs143202281
• NM_001349338.3:c.*3413_*3414dupTG

Variant summary

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

The NM_001349338.3(FOXP1):​c.*3413_*3414dupTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 221,286 control chromosomes in the GnomAD database, including 176 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (174 hom., cov: 26)
  • Exomes 𝑓: 0.044 (2 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 (NFE) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3413_*3414dupTG		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.*3413_*3414dupTG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3413_*3414dupTG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.0482 AC: 7088 AN: 147110 Hom.: 175 Cov.: 26

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.0168

Gnomad AMR AF: 0.0368

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.00796

Gnomad SAS AF: 0.0363

Gnomad FIN AF: 0.0786

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.0555

Gnomad OTH AF: 0.0425

GnomAD4 exome AF: 0.0438 AC: 3245 AN: 74082 Hom.: 2 Cov.: 0 AF XY: 0.0430 AC XY: 1463 AN XY: 34058

African (AFR) AF: 0.0469 AC: 177 AN: 3778

American (AMR) AF: 0.0355 AC: 81 AN: 2284

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 147 AN: 4630

East Asian (EAS) AF: 0.0115 AC: 127 AN: 11046

South Asian (SAS) AF: 0.0379 AC: 27 AN: 712

European-Finnish (FIN) AF: 0.0316 AC: 10 AN: 316

Middle Eastern (MID) AF: 0.0450 AC: 20 AN: 444

European-Non Finnish (NFE) AF: 0.0536 AC: 2397 AN: 44750

Other (OTH) AF: 0.0423 AC: 259 AN: 6122

GnomAD4 genome AF: 0.0482 AC: 7090 AN: 147204 Hom.: 174 Cov.: 26 AF XY: 0.0480 AC XY: 3434 AN XY: 71588

African (AFR) AF: 0.0417 AC: 1685 AN: 40388

American (AMR) AF: 0.0368 AC: 539 AN: 14646

Ashkenazi Jewish (ASJ) AF: 0.0329 AC: 112 AN: 3402

East Asian (EAS) AF: 0.00797 AC: 40 AN: 5016

South Asian (SAS) AF: 0.0367 AC: 170 AN: 4638

European-Finnish (FIN) AF: 0.0786 AC: 750 AN: 9538

Middle Eastern (MID) AF: 0.0241 AC: 7 AN: 290

European-Non Finnish (NFE) AF: 0.0556 AC: 3686 AN: 66348

Other (OTH) AF: 0.0420 AC: 86 AN: 2046

Alfa AF: 0.0270 Hom.: 6

Bravo AF: 0.0438

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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;