NM_014491.4:c.169-11932G>A

Variant names:

• chr7-114522685-G-A
• rs6980093
• NM_014491.4:c.169-11932G>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.169-11932G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 151,990 control chromosomes in the GnomAD database, including 34,756 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 0.66 (34756 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.719
• Publications: 20 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.838 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.169-11932G>A		intron	N/A	NP_055306.1
	FOXP2	NM_148898.4		c.169-11932G>A		intron	N/A	NP_683696.2
	FOXP2	NM_148900.4		c.169-11932G>A		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.169-11932G>A		intron	N/A	ENSP00000265436.7
	FOXP2	ENST00000408937.7	TSL:1	c.169-11932G>A		intron	N/A	ENSP00000386200.3
	FOXP2	ENST00000390668.3	TSL:1	c.166-11932G>A		intron	N/A	ENSP00000375084.3

Frequencies

GnomAD3 genomes AF: 0.665 AC: 100956 AN: 151870 Hom.: 34700 Cov.: 32

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.626

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

GnomAD4 genome AF: 0.665 AC: 101072 AN: 151990 Hom.: 34756 Cov.: 32 AF XY: 0.663 AC XY: 49231 AN XY: 74286

African (AFR) AF: 0.845 AC: 35058 AN: 41490

American (AMR) AF: 0.668 AC: 10193 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 1815 AN: 3470

East Asian (EAS) AF: 0.561 AC: 2902 AN: 5172

South Asian (SAS) AF: 0.720 AC: 3471 AN: 4818

European-Finnish (FIN) AF: 0.549 AC: 5779 AN: 10530

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.588 AC: 39938 AN: 67930

Other (OTH) AF: 0.626 AC: 1319 AN: 2108

Alfa AF: 0.614 Hom.: 59140

Bravo AF: 0.681

Asia WGS AF: 0.637 AC: 2210 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.74
DANN	Benign	0.55
PhyloP100		-0.72
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: rs6980093; hg19: chr7-114162740;