NM_014491.4:c.259-22846T>A

Variant names:

• chr7-114605694-T-A
• rs10230558
• NM_014491.4:c.259-22846T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014491.4(FOXP2):​c.259-22846T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 152,054 control chromosomes in the GnomAD database, including 19,274 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 0.49 (19274 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NM_014491.4	c.259-22846T>A		intron_variant	Intron 3 of 16	ENST00000350908.9	NP_055306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000350908.9	c.259-22846T>A		intron_variant	Intron 3 of 16	1	NM_014491.4	ENSP00000265436.7

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74359 AN: 151936 Hom.: 19267 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.473

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

GnomAD4 genome AF: 0.489 AC: 74390 AN: 152054 Hom.: 19274 Cov.: 32 AF XY: 0.494 AC XY: 36727 AN XY: 74312

African (AFR) AF: 0.320 AC: 13259 AN: 41474

American (AMR) AF: 0.591 AC: 9021 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1347 AN: 3472

East Asian (EAS) AF: 0.744 AC: 3841 AN: 5166

South Asian (SAS) AF: 0.604 AC: 2910 AN: 4814

European-Finnish (FIN) AF: 0.531 AC: 5613 AN: 10574

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36783 AN: 67972

Other (OTH) AF: 0.476 AC: 1003 AN: 2108

Alfa AF: 0.507 Hom.: 2510

Bravo AF: 0.484

Asia WGS AF: 0.639 AC: 2221 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.8
DANN	Benign	0.53
PhyloP100		0.17
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: rs10230558; hg19: chr7-114245749;