3-70956415-CTT-C

Variant names:

• chr3-70956415-CTT-C
• rs112098084
• NM_001349338.3:c.*2830_*2831delAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001349338.3(FOXP1):​c.*2830_*2831delAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0183 in 181,228 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 26)
  • Exomes 𝑓: 0.059 (0 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.961
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*2830_*2831delAA		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.*2830_*2831delAA		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*2830_*2831delAA		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.000445 AC: 56 AN: 125828 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000158

Gnomad ASJ AF: 0.00128

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000515

Gnomad FIN AF: 0.00218

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.00120

GnomAD4 exome AF: 0.0587 AC: 3253 AN: 55396 Hom.: 0 AF XY: 0.0576 AC XY: 1472 AN XY: 25554

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

African (AFR) AF: 0.0744 AC: 192 AN: 2582

American (AMR) AF: 0.0608 AC: 101 AN: 1662

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 182 AN: 3470

East Asian (EAS) AF: 0.0546 AC: 444 AN: 8138

South Asian (SAS) AF: 0.0500 AC: 23 AN: 460

European-Finnish (FIN) AF: 0.0161 AC: 6 AN: 372

Middle Eastern (MID) AF: 0.0506 AC: 18 AN: 356

European-Non Finnish (NFE) AF: 0.0600 AC: 2020 AN: 33690

Other (OTH) AF: 0.0572 AC: 267 AN: 4666

⚠️ 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.

GnomAD4 genome AF: 0.000461 AC: 58 AN: 125832 Hom.: 1 Cov.: 26 AF XY: 0.000595 AC XY: 36 AN XY: 60482

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

African (AFR) AF: 0.000362 AC: 12 AN: 33130

American (AMR) AF: 0.000158 AC: 2 AN: 12666

Ashkenazi Jewish (ASJ) AF: 0.00128 AC: 4 AN: 3128

East Asian (EAS) AF: 0.00 AC: 0 AN: 4088

South Asian (SAS) AF: 0.000519 AC: 2 AN: 3852

European-Finnish (FIN) AF: 0.00218 AC: 15 AN: 6884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 246

European-Non Finnish (NFE) AF: 0.000354 AC: 21 AN: 59354

Other (OTH) AF: 0.00119 AC: 2 AN: 1682

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 45

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.96
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112098084; hg19: chr3-71005566;