NM_014491.4:c.258+39730A>G

Variant names:

• chr7-114574436-A-G
• rs12671308
• NM_014491.4:c.258+39730A>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.258+39730A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 151,646 control chromosomes in the GnomAD database, including 2,476 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 0.12 (2476 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.926
• Publications: 1 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NM_014491.4	c.258+39730A>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.258+39730A>G		intron_variant	Intron 3 of 16	1	NM_014491.4	ENSP00000265436.7

Frequencies

GnomAD3 genomes AF: 0.119 AC: 17964 AN: 151528 Hom.: 2464 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0791

Gnomad ASJ AF: 0.0589

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0962

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

GnomAD4 genome AF: 0.119 AC: 18024 AN: 151646 Hom.: 2476 Cov.: 32 AF XY: 0.119 AC XY: 8783 AN XY: 74100

African (AFR) AF: 0.327 AC: 13524 AN: 41374

American (AMR) AF: 0.0792 AC: 1201 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.0589 AC: 204 AN: 3464

East Asian (EAS) AF: 0.234 AC: 1204 AN: 5148

South Asian (SAS) AF: 0.116 AC: 561 AN: 4826

European-Finnish (FIN) AF: 0.0194 AC: 205 AN: 10592

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0133 AC: 902 AN: 67764

Other (OTH) AF: 0.0957 AC: 201 AN: 2100

Alfa AF: 0.0810 Hom.: 205

Bravo AF: 0.135

Asia WGS AF: 0.179 AC: 622 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.3
DANN	Benign	0.80
PhyloP100		0.93
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: rs12671308; hg19: chr7-114214491;