rs12705966

Variant names:

• chr7-114608796-A-G
• rs12705966
• NM_014491.4:c.259-19744A>G

Variant summary

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

The NM_014491.4(FOXP2):​c.259-19744A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 152,154 control chromosomes in the GnomAD database, including 5,709 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 0.24 (5709 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.223
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NM_014491.4	c.259-19744A>G		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.259-19744A>G		intron_variant	Intron 3 of 16	1	NM_014491.4	ENSP00000265436.7

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36036 AN: 152036 Hom.: 5714 Cov.: 32

Gnomad AFR AF: 0.0568

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.276

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

GnomAD4 genome AF: 0.237 AC: 36029 AN: 152154 Hom.: 5709 Cov.: 32 AF XY: 0.235 AC XY: 17491 AN XY: 74374

African (AFR) AF: 0.0566 AC: 2352 AN: 41552

American (AMR) AF: 0.234 AC: 3584 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1403 AN: 3468

East Asian (EAS) AF: 0.0201 AC: 104 AN: 5186

South Asian (SAS) AF: 0.146 AC: 705 AN: 4822

European-Finnish (FIN) AF: 0.337 AC: 3563 AN: 10584

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23254 AN: 67944

Other (OTH) AF: 0.275 AC: 578 AN: 2104

Alfa AF: 0.321 Hom.: 14216

Bravo AF: 0.223

Asia WGS AF: 0.102 AC: 358 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.76
PhyloP100		-0.22
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: rs12705966; hg19: chr7-114248851;