chr3-70956415-CT-C

Variant names:

• chr3-70956415-CT-C
• rs112098084
• NM_001349338.3:c.*2831delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001349338.3(FOXP1):​c.*2831delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 181,818 control chromosomes in the GnomAD database, including 102 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.048 (99 hom., cov: 26)
  • Exomes 𝑓: 0.24 (3 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0478 AC: 6011 AN: 125836 Hom.: 99 Cov.: 26

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.0698

Gnomad AMR AF: 0.0392

Gnomad ASJ AF: 0.0166

Gnomad EAS AF: 0.0105

Gnomad SAS AF: 0.0592

Gnomad FIN AF: 0.0593

Gnomad MID AF: 0.0331

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.0467

GnomAD4 exome AF: 0.236 AC: 13196 AN: 55978 Hom.: 3 Cov.: 0 AF XY: 0.231 AC XY: 5982 AN XY: 25846

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

African (AFR) AF: 0.267 AC: 684 AN: 2564

American (AMR) AF: 0.230 AC: 392 AN: 1708

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 729 AN: 3498

East Asian (EAS) AF: 0.275 AC: 2206 AN: 8016

South Asian (SAS) AF: 0.228 AC: 108 AN: 474

European-Finnish (FIN) AF: 0.0865 AC: 32 AN: 370

Middle Eastern (MID) AF: 0.218 AC: 76 AN: 348

European-Non Finnish (NFE) AF: 0.229 AC: 7849 AN: 34246

Other (OTH) AF: 0.236 AC: 1120 AN: 4754

⚠️ 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: 0.0478 AC: 6014 AN: 125840 Hom.: 99 Cov.: 26 AF XY: 0.0488 AC XY: 2949 AN XY: 60490

African (AFR) AF: 0.0396 AC: 1313 AN: 33130

American (AMR) AF: 0.0392 AC: 496 AN: 12664

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 52 AN: 3130

East Asian (EAS) AF: 0.0108 AC: 44 AN: 4088

South Asian (SAS) AF: 0.0597 AC: 230 AN: 3854

European-Finnish (FIN) AF: 0.0593 AC: 410 AN: 6912

Middle Eastern (MID) AF: 0.0323 AC: 8 AN: 248

European-Non Finnish (NFE) AF: 0.0560 AC: 3325 AN: 59330

Other (OTH) AF: 0.0476 AC: 80 AN: 1682

Alfa AF: 0.0123 Hom.: 45

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.96
Mutation Taster		=100/0	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;