3-70955832-GCACACACACACA-GCACACACACA

Variant names:

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

Variant summary

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

The NM_001349338.3(FOXP1):​c.*3413_*3414delTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 184,958 control chromosomes in the GnomAD database, including 24 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 26)
  • Exomes 𝑓: 0.071 (3 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.435
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, ClinGen
• 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 afr. GnomAd4 allele frequency = 0.0107 (1573/146912) while in subpopulation AFR AF = 0.0286 (1154/40396). AF 95% confidence interval is 0.0272. There are 21 homozygotes in GnomAd4. There are 757 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1573 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP1	NM_001349338.3	MANE Select	c.*3413_*3414delTG		3_prime_UTR	Exon 21 of 21	NP_001336267.1	Q548T7
	FOXP1	NM_001244810.2		c.*3413_*3414delTG		3_prime_UTR	Exon 21 of 21	NP_001231739.1	Q9H334-8
	FOXP1	NM_001244814.3		c.*3413_*3414delTG		3_prime_UTR	Exon 17 of 17	NP_001231743.1	Q9H334-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP1	ENST00000649528.3	MANE Select	c.*3413_*3414delTG		3_prime_UTR	Exon 21 of 21	ENSP00000497369.1	Q9H334-1
	FOXP1	ENST00000318789.11	TSL:1	c.*3413_*3414delTG		3_prime_UTR	Exon 21 of 21	ENSP00000318902.5	Q9H334-1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1565 AN: 146820 Hom.: 21 Cov.: 26

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00224

Gnomad AMR AF: 0.00562

Gnomad ASJ AF: 0.000589

Gnomad EAS AF: 0.000597

Gnomad SAS AF: 0.00215

Gnomad FIN AF: 0.00222

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00414

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.0705 AC: 2683 AN: 38046 Hom.: 3 AF XY: 0.0721 AC XY: 1242 AN XY: 17232

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

African (AFR) AF: 0.0388 AC: 131 AN: 3374

American (AMR) AF: 0.0664 AC: 84 AN: 1266

Ashkenazi Jewish (ASJ) AF: 0.0830 AC: 163 AN: 1964

East Asian (EAS) AF: 0.0108 AC: 94 AN: 8712

South Asian (SAS) AF: 0.0625 AC: 26 AN: 416

European-Finnish (FIN) AF: 0.0985 AC: 26 AN: 264

Middle Eastern (MID) AF: 0.0556 AC: 13 AN: 234

European-Non Finnish (NFE) AF: 0.102 AC: 1897 AN: 18646

Other (OTH) AF: 0.0785 AC: 249 AN: 3170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0107 AC: 1573 AN: 146912 Hom.: 21 Cov.: 26 AF XY: 0.0106 AC XY: 757 AN XY: 71422

African (AFR) AF: 0.0286 AC: 1154 AN: 40396

American (AMR) AF: 0.00554 AC: 81 AN: 14616

Ashkenazi Jewish (ASJ) AF: 0.000589 AC: 2 AN: 3394

East Asian (EAS) AF: 0.000598 AC: 3 AN: 5014

South Asian (SAS) AF: 0.00194 AC: 9 AN: 4640

European-Finnish (FIN) AF: 0.00222 AC: 21 AN: 9444

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

European-Non Finnish (NFE) AF: 0.00414 AC: 274 AN: 66184

Other (OTH) AF: 0.0127 AC: 26 AN: 2042

Alfa AF: 0.000620 Hom.: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual Disability with Language Impairment and Autistic Features (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143202281; hg19: chr3-71004983; COSMIC: COSV59544990; COSMIC: COSV59544990;