chr3-70956415-C-CT

Variant names:

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

Variant summary

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

The NM_001349338.3(FOXP1):​c.*2831dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 185,698 control chromosomes in the GnomAD database, including 1,571 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1568 hom., cov: 26)
  • Exomes 𝑓: 0.11 (3 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 (NFE) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.150 AC: 18874 AN: 125868 Hom.: 1570 Cov.: 26

Gnomad AFR AF: 0.0568

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.0234

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.114 AC: 6797 AN: 59824 Hom.: 3 Cov.: 0 AF XY: 0.116 AC XY: 3213 AN XY: 27688

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

African (AFR) AF: 0.0617 AC: 172 AN: 2788

American (AMR) AF: 0.112 AC: 199 AN: 1774

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 640 AN: 3694

East Asian (EAS) AF: 0.0377 AC: 345 AN: 9160

South Asian (SAS) AF: 0.106 AC: 53 AN: 500

European-Finnish (FIN) AF: 0.0780 AC: 29 AN: 372

Middle Eastern (MID) AF: 0.143 AC: 54 AN: 378

European-Non Finnish (NFE) AF: 0.130 AC: 4694 AN: 36166

Other (OTH) AF: 0.122 AC: 611 AN: 4992

⚠️ 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: 0.150 AC: 18855 AN: 125874 Hom.: 1568 Cov.: 26 AF XY: 0.147 AC XY: 8894 AN XY: 60504

African (AFR) AF: 0.0568 AC: 1882 AN: 33118

American (AMR) AF: 0.174 AC: 2210 AN: 12674

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 853 AN: 3132

East Asian (EAS) AF: 0.0228 AC: 93 AN: 4086

South Asian (SAS) AF: 0.103 AC: 397 AN: 3840

European-Finnish (FIN) AF: 0.164 AC: 1131 AN: 6912

Middle Eastern (MID) AF: 0.254 AC: 63 AN: 248

European-Non Finnish (NFE) AF: 0.199 AC: 11807 AN: 59380

Other (OTH) AF: 0.159 AC: 267 AN: 1682

Alfa AF: 0.0375 Hom.: 45

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual Disability with Language Impairment and Autistic Features Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;