3-70956489-G-GT

Variant names:

• chr3-70956489-G-GT
• rs886058836
• NM_001349338.3:c.*2757dupA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001349338.3(FOXP1):​c.*2757dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 207,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0087 (0 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000364 (52/142722) while in subpopulation AFR AF = 0.000846 (33/39010). AF 95% confidence interval is 0.000619. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*2757dupA		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.*2757dupA		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*2757dupA		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.000365 AC: 52 AN: 142632 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000848

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000353

Gnomad ASJ AF: 0.000596

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000670

Gnomad FIN AF: 0.000116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000123

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00869 AC: 560 AN: 64468 Hom.: 0 Cov.: 0 AF XY: 0.00802 AC XY: 238 AN XY: 29674

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

African (AFR) AF: 0.0114 AC: 35 AN: 3058

American (AMR) AF: 0.0136 AC: 26 AN: 1912

Ashkenazi Jewish (ASJ) AF: 0.00718 AC: 29 AN: 4038

East Asian (EAS) AF: 0.00554 AC: 52 AN: 9392

South Asian (SAS) AF: 0.00929 AC: 5 AN: 538

European-Finnish (FIN) AF: 0.00427 AC: 2 AN: 468

Middle Eastern (MID) AF: 0.00815 AC: 3 AN: 368

European-Non Finnish (NFE) AF: 0.00924 AC: 364 AN: 39410

Other (OTH) AF: 0.00833 AC: 44 AN: 5284

⚠️ 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: 0.000364 AC: 52 AN: 142722 Hom.: 0 Cov.: 29 AF XY: 0.000404 AC XY: 28 AN XY: 69298

African (AFR) AF: 0.000846 AC: 33 AN: 39010

American (AMR) AF: 0.000352 AC: 5 AN: 14190

Ashkenazi Jewish (ASJ) AF: 0.000596 AC: 2 AN: 3354

East Asian (EAS) AF: 0.00 AC: 0 AN: 4860

South Asian (SAS) AF: 0.000672 AC: 3 AN: 4464

European-Finnish (FIN) AF: 0.000116 AC: 1 AN: 8650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000123 AC: 8 AN: 65090

Other (OTH) AF: 0.00 AC: 0 AN: 1950

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=100/0	polymorphism

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: rs886058836; hg19: chr3-71005640; COSMIC: COSV100561240; COSMIC: COSV100561240;