rs2253478

Variant names:

• chr7-114337941-A-G
• rs2253478
• ENST00000440349.5:n.-11+49832A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000440349.5(FOXP2):​n.-11+49832A>G variant causes a intron change. The variant allele was found at a frequency of 0.59 in 150,742 control chromosomes in the GnomAD database, including 26,745 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.59 (26745 hom., cov: 31)
• Consequence: FOXP2 ENST00000440349.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74
• Publications: 9 publications found

Genes affected

FOXP2 (HGNC:13875): (forkhead box P2) This gene encodes a member of the forkhead/winged-helix (FOX) family of transcription factors. It is expressed in fetal and adult brain as well as in several other organs such as the lung and gut. The protein product contains a FOX DNA-binding domain and a large polyglutamine tract and is an evolutionarily conserved transcription factor, which may bind directly to approximately 300 to 400 gene promoters in the human genome to regulate the expression of a variety of genes. This gene is required for proper development of speech and language regions of the brain during embryogenesis, and may be involved in a variety of biological pathways and cascades that may ultimately influence language development. Mutations in this gene cause speech-language disorder 1 (SPCH1), also known as autosomal dominant speech and language disorder with orofacial dyspraxia. Multiple alternative transcripts encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

FOXP2 Gene-Disease associations (from GenCC):

• specific language disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood apraxia of speech

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NR_033766.2	n.376+49832A>G		intron_variant	Intron 2 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000440349.5	n.-11+49832A>G		intron_variant	Intron 3 of 11	1		ENSP00000395552.1
FOXP2	ENST00000703616.1	c.-11+49832A>G		intron_variant	Intron 3 of 20			ENSP00000515400.1
FOXP2	ENST00000703613.1	c.-11+49832A>G		intron_variant	Intron 4 of 20			ENSP00000515397.1

Frequencies

GnomAD3 genomes AF: 0.590 AC: 88899 AN: 150622 Hom.: 26719 Cov.: 31

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.602

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.590 AC: 88968 AN: 150742 Hom.: 26745 Cov.: 31 AF XY: 0.598 AC XY: 44023 AN XY: 73674

African (AFR) AF: 0.489 AC: 20196 AN: 41338

American (AMR) AF: 0.614 AC: 9272 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2516 AN: 3446

East Asian (EAS) AF: 0.838 AC: 4322 AN: 5156

South Asian (SAS) AF: 0.717 AC: 3458 AN: 4826

European-Finnish (FIN) AF: 0.638 AC: 6723 AN: 10532

Middle Eastern (MID) AF: 0.651 AC: 190 AN: 292

European-Non Finnish (NFE) AF: 0.603 AC: 40441 AN: 67054

Other (OTH) AF: 0.603 AC: 1256 AN: 2082

Alfa AF: 0.585 Hom.: 3751

Bravo AF: 0.581

Asia WGS AF: 0.766 AC: 2660 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.88
PhyloP100		4.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2253478; hg19: chr7-113977996;