Genetic Variant NM_001349338.3:c.*2827_*2831delAAAAA (chr3-70956415-CTTTTT-C) – 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.*2827_*2831delAAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 186,524 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 0.000079 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00066 ( 0 hom. )

Consequence

FOXP1
NM_001349338.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.68

Publications

0 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 nfe. GnomAd4 allele frequency = 0.0000794 (10/125954) while in subpopulation NFE AF = 0.000152 (9/59402). AF 95% confidence interval is 0.000079. 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 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3 link	c.2827_2831delAAAAA		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.2827_2831delAAAAA		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1		Q9H334-1
FOXP1	ENST00000318789.11 link	c.2827_2831delAAAAA		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5		Q9H334-1

Frequencies

GnomAD3 genomes

AF:

0.0000794

AC:

AN:

125950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000145

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000660

AC:

AN:

60570

Hom.:

AF XY:

0.000678

AC XY:

AN XY:

28006

show subpopulations

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

African (AFR)

AF:

0.000714

AC:

AN:

2802

American (AMR)

AF:

0.00111

AC:

AN:

1804

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

3736

East Asian (EAS)

AF:

0.000108

AC:

AN:

9278

South Asian (SAS)

AF:

0.00197

AC:

AN:

508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

380

European-Non Finnish (NFE)

AF:

0.000683

AC:

AN:

36626

Other (OTH)

AF:

0.000791

AC:

AN:

5058

⚠️ 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: 0.285

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000794

AC:

AN:

125954

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

60548

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33152

American (AMR)

AF:

0.00

AC:

AN:

12676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3132

East Asian (EAS)

AF:

0.00

AC:

AN:

4088

South Asian (SAS)

AF:

0.00

AC:

AN:

3852

European-Finnish (FIN)

AF:

0.000145

AC:

AN:

6918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

248

European-Non Finnish (NFE)

AF:

0.000152

AC:

AN:

59402

Other (OTH)

AF:

0.00

AC:

AN:

1684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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

1.7

Splicing

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

Publications

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NM_001349338.3:c.2827_2831delAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over