3-70955832-GCACACACACACA-GCACACACACACACACA

Variant names:

• chr3-70955832-G-GCACA
• rs143202281
• NM_001349338.3:c.*3411_*3414dupTGTG

Variant summary

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

The NM_001349338.3(FOXP1):​c.*3411_*3414dupTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 221,522 control chromosomes in the GnomAD database, including 100 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (100 hom., cov: 26)
  • Exomes 𝑓: 0.0057 (0 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 (AFR) allele frequency at 95% confidence interval = 0.0625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3411_*3414dupTGTG		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.*3411_*3414dupTGTG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3411_*3414dupTGTG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 2937 AN: 147146 Hom.: 100 Cov.: 26

Gnomad AFR AF: 0.0646

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0128

GnomAD4 exome AF: 0.00568 AC: 422 AN: 74282 Hom.: 0 Cov.: 0 AF XY: 0.00510 AC XY: 174 AN XY: 34128

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

African (AFR) AF: 0.0693 AC: 259 AN: 3740

American (AMR) AF: 0.0140 AC: 32 AN: 2288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4646

East Asian (EAS) AF: 0.000814 AC: 9 AN: 11050

South Asian (SAS) AF: 0.0140 AC: 10 AN: 712

European-Finnish (FIN) AF: 0.00316 AC: 1 AN: 316

Middle Eastern (MID) AF: 0.00673 AC: 3 AN: 446

European-Non Finnish (NFE) AF: 0.00129 AC: 58 AN: 44948

Other (OTH) AF: 0.00815 AC: 50 AN: 6136

⚠️ 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: 0.0200 AC: 2941 AN: 147240 Hom.: 100 Cov.: 26 AF XY: 0.0203 AC XY: 1457 AN XY: 71606

African (AFR) AF: 0.0646 AC: 2608 AN: 40386

American (AMR) AF: 0.0103 AC: 151 AN: 14650

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

East Asian (EAS) AF: 0.00140 AC: 7 AN: 5016

South Asian (SAS) AF: 0.0151 AC: 70 AN: 4640

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

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.00116 AC: 77 AN: 66364

Other (OTH) AF: 0.0132 AC: 27 AN: 2046

Alfa AF: 0.000689 Hom.: 6

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

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;