3-70955570-GTTTT-GTTTTT

Variant names:

• chr3-70955570-G-GT
• rs35502550
• NM_001349338.3:c.*3676dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001349338.3(FOXP1):​c.*3676dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 197,416 control chromosomes in the GnomAD database, including 2,749 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (2717 hom., cov: 30)
  • Exomes 𝑓: 0.40 (32 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.620
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 3-70955570-G-GT is Benign according to our data. Variant chr3-70955570-G-GT is described in ClinVar as [Benign]. Clinvar id is 346554.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3676dupA		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.*3676dupA		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*3676dupA		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.140 AC: 20204 AN: 144272 Hom.: 2713 Cov.: 30

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.0101

Gnomad AMR AF: 0.0975

Gnomad ASJ AF: 0.0497

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0832

Gnomad MID AF: 0.0676

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.403 AC: 21373 AN: 53098 Hom.: 32 Cov.: 0 AF XY: 0.402 AC XY: 9782 AN XY: 24332

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

African (AFR) AF: 0.400 AC: 1256 AN: 3140

American (AMR) AF: 0.398 AC: 661 AN: 1660

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1230 AN: 3200

East Asian (EAS) AF: 0.473 AC: 4431 AN: 9376

South Asian (SAS) AF: 0.429 AC: 213 AN: 496

European-Finnish (FIN) AF: 0.124 AC: 21 AN: 170

Middle Eastern (MID) AF: 0.403 AC: 125 AN: 310

European-Non Finnish (NFE) AF: 0.386 AC: 11744 AN: 30390

Other (OTH) AF: 0.388 AC: 1692 AN: 4356

⚠️ 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: 0.140 AC: 20230 AN: 144318 Hom.: 2717 Cov.: 30 AF XY: 0.144 AC XY: 10090 AN XY: 70170

African (AFR) AF: 0.309 AC: 12373 AN: 39980

American (AMR) AF: 0.0973 AC: 1399 AN: 14382

Ashkenazi Jewish (ASJ) AF: 0.0497 AC: 166 AN: 3342

East Asian (EAS) AF: 0.494 AC: 2482 AN: 5028

South Asian (SAS) AF: 0.165 AC: 753 AN: 4562

European-Finnish (FIN) AF: 0.0832 AC: 734 AN: 8826

Middle Eastern (MID) AF: 0.0735 AC: 20 AN: 272

European-Non Finnish (NFE) AF: 0.0315 AC: 2047 AN: 65056

Other (OTH) AF: 0.125 AC: 247 AN: 1982

Alfa AF: 0.00659 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual Disability with Language Impairment and Autistic Features Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

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		0.62
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: rs35502550; hg19: chr3-71004721;