rs12154391

Variant names:

• chr7-114660662-T-C
• rs12154391
• NM_014491.4:c.1647+989T>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.1647+989T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 152,044 control chromosomes in the GnomAD database, including 9,826 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 0.33 (9826 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90
• Publications: 4 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=-0.52).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NM_014491.4	c.1647+989T>C		intron_variant	Intron 13 of 16	ENST00000350908.9	NP_055306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000350908.9	c.1647+989T>C		intron_variant	Intron 13 of 16	1	NM_014491.4	ENSP00000265436.7

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50435 AN: 151926 Hom.: 9828 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.304

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

GnomAD4 genome AF: 0.332 AC: 50441 AN: 152044 Hom.: 9826 Cov.: 32 AF XY: 0.329 AC XY: 24427 AN XY: 74308

African (AFR) AF: 0.144 AC: 5959 AN: 41518

American (AMR) AF: 0.307 AC: 4689 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 991 AN: 3470

East Asian (EAS) AF: 0.142 AC: 734 AN: 5176

South Asian (SAS) AF: 0.314 AC: 1516 AN: 4822

European-Finnish (FIN) AF: 0.454 AC: 4789 AN: 10544

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30721 AN: 67932

Other (OTH) AF: 0.302 AC: 638 AN: 2116

Alfa AF: 0.393 Hom.: 18397

Bravo AF: 0.311

Asia WGS AF: 0.232 AC: 804 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.71
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs12154391; hg19: chr7-114300717;