chr7-114094981-A-C

Variant names:

• chr7-114094981-A-C
• rs923875
• ENST00000440349.5:n.-247+8370A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000440349.5(FOXP2):​n.-247+8370A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 152,010 control chromosomes in the GnomAD database, including 17,832 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 0.47 (17832 hom., cov: 32)
• Consequence: FOXP2 ENST00000440349.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.645
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NR_033766.2	n.285+8370A>C		intron_variant	Intron 1 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000440349.5	n.-247+8370A>C		intron_variant	Intron 1 of 11	1		ENSP00000395552.1
FOXP2	ENST00000703616.1	c.-247+7143A>C		intron_variant	Intron 1 of 20			ENSP00000515400.1
FOXP2	ENST00000703613.1	c.-365+8370A>C		intron_variant	Intron 1 of 20			ENSP00000515397.1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71865 AN: 151892 Hom.: 17802 Cov.: 32

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.464

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

GnomAD4 genome AF: 0.473 AC: 71948 AN: 152010 Hom.: 17832 Cov.: 32 AF XY: 0.476 AC XY: 35349 AN XY: 74294

African (AFR) AF: 0.610 AC: 25291 AN: 41458

American (AMR) AF: 0.431 AC: 6579 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1508 AN: 3470

East Asian (EAS) AF: 0.588 AC: 3035 AN: 5158

South Asian (SAS) AF: 0.393 AC: 1890 AN: 4806

European-Finnish (FIN) AF: 0.418 AC: 4415 AN: 10564

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27773 AN: 67970

Other (OTH) AF: 0.462 AC: 975 AN: 2110

Alfa AF: 0.422 Hom.: 4953

Bravo AF: 0.479

Asia WGS AF: 0.494 AC: 1712 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.63
DANN	Benign	0.73
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs923875; hg19: chr7-113735036;