3-70955832-GCACACACACACA-GCACACACACA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting 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: Illumina, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1573 AD gene.

Transcripts

RefSeq

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

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 = 0.000000), 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

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		0.43
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;