chr7-114663134-G-A

Variant names:

• chr7-114663134-G-A
• rs1563408
• NM_014491.4:c.1770-316G>A

Variant summary

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

The NM_014491.4(FOXP2):​c.1770-316G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 151,782 control chromosomes in the GnomAD database, including 12,414 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 0.39 (12414 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109
• Publications: 7 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)

ENSG00000303050 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.472 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.1770-316G>A		intron	N/A	NP_055306.1
	FOXP2	NM_148898.4		c.1845-316G>A		intron	N/A	NP_683696.2
	FOXP2	NM_148900.4		c.1821-316G>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.1770-316G>A		intron	N/A	ENSP00000265436.7
	FOXP2	ENST00000408937.7	TSL:1	c.1845-316G>A		intron	N/A	ENSP00000386200.3
	FOXP2	ENST00000393489.8	TSL:1	n.*1564-316G>A		intron	N/A	ENSP00000377129.4

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59255 AN: 151664 Hom.: 12409 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.368

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

GnomAD4 genome AF: 0.391 AC: 59300 AN: 151782 Hom.: 12414 Cov.: 32 AF XY: 0.393 AC XY: 29108 AN XY: 74148

African (AFR) AF: 0.237 AC: 9810 AN: 41410

American (AMR) AF: 0.384 AC: 5843 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1133 AN: 3468

East Asian (EAS) AF: 0.488 AC: 2514 AN: 5156

South Asian (SAS) AF: 0.456 AC: 2193 AN: 4812

European-Finnish (FIN) AF: 0.476 AC: 5006 AN: 10524

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31606 AN: 67890

Other (OTH) AF: 0.369 AC: 777 AN: 2108

Alfa AF: 0.434 Hom.: 54825

Bravo AF: 0.376

Asia WGS AF: 0.464 AC: 1607 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.2
DANN	Benign	0.46
PhyloP100		0.11
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: rs1563408; hg19: chr7-114303189;