3-70955830-G-GCACACA

Variant names:

• chr3-70955830-G-GCACACA
• rs886058826
• NM_001349338.3:c.*3416_*3417insTGTGTG

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.*3416_*3417insTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 205,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (0 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.829
• 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 eas. GnomAd4 allele frequency = 0.00201 (255/126568) while in subpopulation EAS AF = 0.01 (37/3686). AF 95% confidence interval is 0.00815. There are 0 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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 255 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3416_*3417insTGTGTG		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.*3416_*3417insTGTGTG		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3416_*3417insTGTGTG		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 255 AN: 126514 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00918

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00112

GnomAD4 exome AF: 0.000934 AC: 74 AN: 79200 Hom.: 0 Cov.: 0 AF XY: 0.000959 AC XY: 35 AN XY: 36490

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

African (AFR) AF: 0.00783 AC: 27 AN: 3450

American (AMR) AF: 0.000415 AC: 1 AN: 2412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5032

East Asian (EAS) AF: 0.00361 AC: 38 AN: 10518

South Asian (SAS) AF: 0.00 AC: 0 AN: 772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 486

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 49546

Other (OTH) AF: 0.00121 AC: 8 AN: 6614

⚠️ 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: 0.00201 AC: 255 AN: 126568 Hom.: 0 Cov.: 32 AF XY: 0.00177 AC XY: 109 AN XY: 61708

African (AFR) AF: 0.00915 AC: 213 AN: 23266

American (AMR) AF: 0.000148 AC: 2 AN: 13526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3334

East Asian (EAS) AF: 0.0100 AC: 37 AN: 3686

South Asian (SAS) AF: 0.00 AC: 0 AN: 4200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65912

Other (OTH) AF: 0.00111 AC: 2 AN: 1804

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		0.83

Splicing

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

Other links and lift over

dbSNP: rs886058826; hg19: chr3-71004981;