7-114538975-A-G

Variant names:

• chr7-114538975-A-G
• rs35487108
• NM_014491.4:c.258+4269A>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+4269A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0884 in 151,886 control chromosomes in the GnomAD database, including 1,242 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 0.088 (1242 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.41
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 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+4269A>G		intron	N/A	NP_055306.1
	FOXP2	NM_148898.4		c.258+4269A>G		intron	N/A	NP_683696.2
	FOXP2	NM_148900.4		c.258+4269A>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+4269A>G		intron	N/A	ENSP00000265436.7
	FOXP2	ENST00000408937.7	TSL:1	c.258+4269A>G		intron	N/A	ENSP00000386200.3
	FOXP2	ENST00000390668.3	TSL:1	c.255+4269A>G		intron	N/A	ENSP00000375084.3

Frequencies

GnomAD3 genomes AF: 0.0882 AC: 13388 AN: 151768 Hom.: 1235 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0663

Gnomad ASJ AF: 0.0525

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0717

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

GnomAD4 genome AF: 0.0884 AC: 13423 AN: 151886 Hom.: 1242 Cov.: 32 AF XY: 0.0886 AC XY: 6575 AN XY: 74246

African (AFR) AF: 0.231 AC: 9571 AN: 41454

American (AMR) AF: 0.0664 AC: 1010 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 182 AN: 3466

East Asian (EAS) AF: 0.157 AC: 813 AN: 5166

South Asian (SAS) AF: 0.118 AC: 570 AN: 4824

European-Finnish (FIN) AF: 0.0159 AC: 168 AN: 10592

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0138 AC: 935 AN: 67850

Other (OTH) AF: 0.0724 AC: 153 AN: 2114

Alfa AF: 0.0237 Hom.: 31

Bravo AF: 0.101

Asia WGS AF: 0.137 AC: 472 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.84
PhyloP100		3.4
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: rs35487108; hg19: chr7-114179030;