Genetic Variant NM_001349338.3:c.*3416_*3417insTGTGTGTGTG (chr3-70955830-G-GCACACACACA) – 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.*3416_*3417insTGTGTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 205,662 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 0 hom. )

Consequence

FOXP1
NM_001349338.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.829

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 eas. GnomAd4 allele frequency = 0.00157 (199/126572) while in subpopulation EAS AF = 0.0427 (157/3680). AF 95% confidence interval is 0.0372. There are 1 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3 link	c.3416_3417insTGTGTGTGTG		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.3416_3417insTGTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1		Q9H334-1
FOXP1	ENST00000318789.11 link	c.3416_3417insTGTGTGTGTG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5		Q9H334-1

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

200

AN:

126518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000431

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000666

Gnomad ASJ

AF:

0.000300

Gnomad EAS

AF:

0.0428

Gnomad SAS

AF:

0.00595

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000607

Gnomad OTH

AF:

0.00112

GnomAD4 exome

AF:

0.00564

AC:

446

AN:

79090

Hom.:

Cov.:

AF XY:

0.00519

AC XY:

189

AN XY:

36442

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:

3450

American (AMR)

AF:

0.00

AC:

AN:

2412

Ashkenazi Jewish (ASJ)

AF:

0.000199

AC:

AN:

5032

East Asian (EAS)

AF:

0.0415

AC:

432

AN:

10412

South Asian (SAS)

AF:

0.00259

AC:

AN:

772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

370

Middle Eastern (MID)

AF:

0.00412

AC:

AN:

486

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

49542

Other (OTH)

AF:

0.00121

AC:

AN:

6614

⚠️ 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: 0.298

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00157

AC:

199

AN:

126572

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

121

AN XY:

61710

show subpopulations

African (AFR)

AF:

0.0000430

AC:

AN:

23278

American (AMR)

AF:

0.000665

AC:

AN:

13526

Ashkenazi Jewish (ASJ)

AF:

0.000300

AC:

AN:

3334

East Asian (EAS)

AF:

0.0427

AC:

157

AN:

3680

South Asian (SAS)

AF:

0.00596

AC:

AN:

4198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9664

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.0000607

AC:

AN:

65912

Other (OTH)

AF:

0.00111

AC:

AN:

1804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

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

0.83

Splicing

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

Publications

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NM_001349338.3:c.3416_3417insTGTGTGTGTG

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