chr7-114531090-A-G

Variant names:

• chr7-114531090-A-G
• rs9332390
• NM_014491.4:c.169-3527A>G

Variant summary

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

The NM_014491.4(FOXP2):​c.169-3527A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 151,476 control chromosomes in the GnomAD database, including 15,824 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 0.45 (15824 hom., cov: 31)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 4 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.514 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	NM_014491.4	MANE Select	c.169-3527A>G		intron	N/A	NP_055306.1	O15409-1
	FOXP2	NM_148898.4		c.169-3527A>G		intron	N/A	NP_683696.2	O15409-4
	FOXP2	NM_148900.4		c.169-3527A>G		intron	N/A	NP_683698.2	O15409-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	ENST00000350908.9	TSL:1 MANE Select	c.169-3527A>G		intron	N/A	ENSP00000265436.7	O15409-1
	FOXP2	ENST00000408937.7	TSL:1	c.169-3527A>G		intron	N/A	ENSP00000386200.3	O15409-4
	FOXP2	ENST00000390668.3	TSL:1	c.166-3527A>G		intron	N/A	ENSP00000375084.3	Q8N6B5

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68760 AN: 151358 Hom.: 15819 Cov.: 31

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.438

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

GnomAD4 genome AF: 0.454 AC: 68792 AN: 151476 Hom.: 15824 Cov.: 31 AF XY: 0.453 AC XY: 33544 AN XY: 74052

African (AFR) AF: 0.426 AC: 17619 AN: 41366

American (AMR) AF: 0.524 AC: 7940 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1090 AN: 3460

East Asian (EAS) AF: 0.405 AC: 2086 AN: 5146

South Asian (SAS) AF: 0.467 AC: 2251 AN: 4824

European-Finnish (FIN) AF: 0.422 AC: 4462 AN: 10564

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.472 AC: 31929 AN: 67656

Other (OTH) AF: 0.438 AC: 921 AN: 2102

Alfa AF: 0.455 Hom.: 2062

Bravo AF: 0.459

Asia WGS AF: 0.432 AC: 1503 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.91
PhyloP100		1.2
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: rs9332390; hg19: chr7-114171145;