Genetic Variant NM_001349338.3:c.*3414_*3415insTGTGTGTGCG (chr3-70955832-G-GCGCACACACA) – 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.*3414_*3415insTGTGTGTGCG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 221,622 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 26)

Exomes 𝑓: 0.00069 ( 0 hom. )

Consequence

FOXP1
NM_001349338.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.373

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 afr. GnomAd4 allele frequency = 0.00261 (385/147258) while in subpopulation AFR AF = 0.00859 (347/40402). AF 95% confidence interval is 0.00784. There are 2 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 385 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3 link	c.3414_3415insTGTGTGTGCG		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.3414_3415insTGTGTGTGCG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1		Q9H334-1
FOXP1	ENST00000318789.11 link	c.3414_3415insTGTGTGTGCG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5		Q9H334-1

Frequencies

GnomAD3 genomes

AF:

0.00262

AC:

386

AN:

147162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00864

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00109

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000796

Gnomad SAS

AF:

0.000645

Gnomad FIN

AF:

0.000314

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000151

Gnomad OTH

AF:

0.000988

GnomAD4 exome

AF:

0.000686

AC:

AN:

74364

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

34160

show subpopulations

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

African (AFR)

AF:

0.00840

AC:

AN:

3810

American (AMR)

AF:

0.00175

AC:

AN:

2292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4646

East Asian (EAS)

AF:

0.000362

AC:

AN:

11048

South Asian (SAS)

AF:

0.00

AC:

AN:

712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

316

Middle Eastern (MID)

AF:

0.00224

AC:

AN:

446

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

44952

Other (OTH)

AF:

0.000651

AC:

AN:

6142

⚠️ 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: 0.346

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00261

AC:

385

AN:

147258

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

174

AN XY:

71616

show subpopulations

African (AFR)

AF:

0.00859

AC:

347

AN:

40402

American (AMR)

AF:

0.00109

AC:

AN:

14652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.000797

AC:

AN:

5016

South Asian (SAS)

AF:

0.000647

AC:

AN:

4640

European-Finnish (FIN)

AF:

0.000314

AC:

AN:

9552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000151

AC:

AN:

66364

Other (OTH)

AF:

0.000978

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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

0.37

Splicing

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

Publications

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NM_001349338.3:c.3414_3415insTGTGTGTGCG

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