NM_014491.4:c.1095-1843T>C

Variant names:

• chr7-114650360-T-C
• rs7782412
• NM_014491.4:c.1095-1843T>C

Variant summary

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

The NM_014491.4(FOXP2):​c.1095-1843T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 151,902 control chromosomes in the GnomAD database, including 10,870 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 0.36 (10870 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.919
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NM_014491.4	c.1095-1843T>C		intron_variant	Intron 8 of 16	ENST00000350908.9	NP_055306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000350908.9	c.1095-1843T>C		intron_variant	Intron 8 of 16	1	NM_014491.4	ENSP00000265436.7

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55359 AN: 151786 Hom.: 10878 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.0311

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.386

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

GnomAD4 genome AF: 0.364 AC: 55358 AN: 151902 Hom.: 10870 Cov.: 32 AF XY: 0.359 AC XY: 26661 AN XY: 74230

African (AFR) AF: 0.291 AC: 12042 AN: 41442

American (AMR) AF: 0.360 AC: 5483 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1659 AN: 3468

East Asian (EAS) AF: 0.0314 AC: 162 AN: 5162

South Asian (SAS) AF: 0.204 AC: 983 AN: 4828

European-Finnish (FIN) AF: 0.417 AC: 4389 AN: 10536

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.431 AC: 29264 AN: 67944

Other (OTH) AF: 0.384 AC: 808 AN: 2106

Alfa AF: 0.409 Hom.: 20981

Bravo AF: 0.361

Asia WGS AF: 0.144 AC: 502 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.8
DANN	Benign	0.66
PhyloP100		0.92
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: rs7782412; hg19: chr7-114290415;