3-70955524-GA-G

Variant names:

• chr3-70955524-GA-G
• rs886058821
• NM_001349338.3:c.*3722delT

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.*3722delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 225,478 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.909
• Publications: 0 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 eas. GnomAd4 allele frequency = 0.0000476 (7/146970) while in subpopulation EAS AF = 0.0004 (2/4998). AF 95% confidence interval is 0.0000706. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3722delT		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.*3722delT		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3722delT		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.0000476 AC: 7 AN: 146926 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000672

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000399

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000892 AC: 7 AN: 78508 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 36142

African (AFR) AF: 0.000266 AC: 1 AN: 3754

American (AMR) AF: 0.00 AC: 0 AN: 2394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4928

East Asian (EAS) AF: 0.0000905 AC: 1 AN: 11046

South Asian (SAS) AF: 0.00 AC: 0 AN: 682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 80

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 482

European-Non Finnish (NFE) AF: 0.0000618 AC: 3 AN: 48554

Other (OTH) AF: 0.000304 AC: 2 AN: 6588

GnomAD4 genome AF: 0.0000476 AC: 7 AN: 146970 Hom.: 0 Cov.: 32 AF XY: 0.0000280 AC XY: 2 AN XY: 71398

African (AFR) AF: 0.0000998 AC: 4 AN: 40064

American (AMR) AF: 0.0000672 AC: 1 AN: 14890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.000400 AC: 2 AN: 4998

South Asian (SAS) AF: 0.00 AC: 0 AN: 4660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66824

Other (OTH) AF: 0.00 AC: 0 AN: 2024

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

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		0.91

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: rs886058821; hg19: chr3-71004675;