chr3-70955832-G-GCGCACA

Variant names:

• chr3-70955832-G-GCGCACA
• rs1553648184
• NM_001349338.3:c.*3414_*3415insTGTGCG

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.*3414_*3415insTGTGCG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 221,612 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 26)
  • Exomes 𝑓: 0.00090 (0 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.373
• 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 = 0.00452 (666/147254) while in subpopulation AFR AF = 0.0152 (616/40398). AF 95% confidence interval is 0.0143. There are 5 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 26. 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 666 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3414_*3415insTGTGCG		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.*3414_*3415insTGTGCG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3414_*3415insTGTGCG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 662 AN: 147158 Hom.: 5 Cov.: 26

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00260

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000753

Gnomad OTH AF: 0.00346

GnomAD4 exome AF: 0.000901 AC: 67 AN: 74358 Hom.: 0 Cov.: 0 AF XY: 0.000761 AC XY: 26 AN XY: 34160

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

African (AFR) AF: 0.0145 AC: 55 AN: 3804

American (AMR) AF: 0.00175 AC: 4 AN: 2290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4646

East Asian (EAS) AF: 0.00 AC: 0 AN: 11050

South Asian (SAS) AF: 0.00 AC: 0 AN: 712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 446

European-Non Finnish (NFE) AF: 0.0000222 AC: 1 AN: 44954

Other (OTH) AF: 0.00114 AC: 7 AN: 6140

⚠️ 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: 0.00452 AC: 666 AN: 147254 Hom.: 5 Cov.: 26 AF XY: 0.00450 AC XY: 322 AN XY: 71612

African (AFR) AF: 0.0152 AC: 616 AN: 40398

American (AMR) AF: 0.00259 AC: 38 AN: 14652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 5016

South Asian (SAS) AF: 0.00 AC: 0 AN: 4640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000753 AC: 5 AN: 66364

Other (OTH) AF: 0.00342 AC: 7 AN: 2046

Alfa AF: 0.00 Hom.: 0

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		0.37

Splicing

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

Other links and lift over

dbSNP: rs1553648184; hg19: chr3-71004983;