Genetic Variant FOXP1:c.*3407_*3414delTGTGTGTG (chr3-70955832-GCACACACA-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001349338.3(FOXP1):c.*3407_*3414delTGTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 221,536 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

FOXP1
NM_001349338.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Publications

3 publications found

Variant links:

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

FOXP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000034 (5/147168) while in subpopulation AMR AF = 0.0000683 (1/14636). AF 95% confidence interval is 0.000012. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3 link	c.3407_3414delTGTGTGTG		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 link	c.3407_3414delTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1		Q9H334-1
FOXP1	ENST00000318789.11 link	c.3407_3414delTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5		Q9H334-1

Frequencies

GnomAD3 genomes

AF:

0.0000340

AC:

AN:

147168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000683

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000452

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000134

AC:

AN:

74368

Hom.:

AF XY:

0.00

AC XY:

AN XY:

34158

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

3810

American (AMR)

AF:

0.00

AC:

AN:

2292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4646

East Asian (EAS)

AF:

0.00

AC:

AN:

11050

South Asian (SAS)

AF:

0.00

AC:

AN:

712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

446

European-Non Finnish (NFE)

AF:

0.0000222

AC:

AN:

44952

Other (OTH)

AF:

0.00

AC:

AN:

6144

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000340

AC:

AN:

147168

Hom.:

Cov.:

AF XY:

0.0000559

AC XY:

AN XY:

71512

show subpopulations

African (AFR)

AF:

0.0000248

AC:

AN:

40292

American (AMR)

AF:

0.0000683

AC:

AN:

14636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

5028

South Asian (SAS)

AF:

0.00

AC:

AN:

4654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000452

AC:

AN:

66374

Other (OTH)

AF:

0.00

AC:

AN:

2024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Splicing

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

Publications

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3-70955832-GCACACACACACA-GCACA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over