chr7-114574299-A-G

Variant names:

• chr7-114574299-A-G
• rs12671286
• NM_014491.4:c.258+39593A>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+39593A>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 151,814 control chromosomes in the GnomAD database, including 2,475 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 (2475 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0690
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014491.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	NM_014491.4	MANE Select	c.258+39593A>G		intron	N/A	NP_055306.1
	FOXP2	NM_148898.4		c.333+3418A>G		intron	N/A	NP_683696.2
	FOXP2	NM_148900.4		c.258+39593A>G		intron	N/A	NP_683698.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	ENST00000350908.9	TSL:1 MANE Select	c.258+39593A>G		intron	N/A	ENSP00000265436.7
	FOXP2	ENST00000408937.7	TSL:1	c.333+3418A>G		intron	N/A	ENSP00000386200.3
	FOXP2	ENST00000390668.3	TSL:1	c.330+3418A>G		intron	N/A	ENSP00000375084.3

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17959 AN: 151696 Hom.: 2463 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0787

Gnomad ASJ AF: 0.0589

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0976

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

GnomAD4 genome AF: 0.119 AC: 18019 AN: 151814 Hom.: 2475 Cov.: 32 AF XY: 0.118 AC XY: 8776 AN XY: 74196

African (AFR) AF: 0.326 AC: 13521 AN: 41420

American (AMR) AF: 0.0788 AC: 1198 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.0589 AC: 204 AN: 3466

East Asian (EAS) AF: 0.232 AC: 1201 AN: 5166

South Asian (SAS) AF: 0.116 AC: 560 AN: 4828

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0133 AC: 904 AN: 67814

Other (OTH) AF: 0.0971 AC: 204 AN: 2102

Alfa AF: 0.0409 Hom.: 529

Bravo AF: 0.135

Asia WGS AF: 0.177 AC: 613 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.31
PhyloP100		-0.069
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: rs12671286; hg19: chr7-114214354;