rs58552483

Variant names:

• chr7-114507726-C-T
• rs58552483
• NM_014491.4:c.169-26891C>T

Variant summary

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

The NM_014491.4(FOXP2):​c.169-26891C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0874 in 151,892 control chromosomes in the GnomAD database, including 1,202 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 0.087 (1202 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.546
• Publications: 2 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 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.169-26891C>T		intron	N/A	NP_055306.1
	FOXP2	NM_148898.4		c.169-26891C>T		intron	N/A	NP_683696.2
	FOXP2	NM_148900.4		c.169-26891C>T		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.169-26891C>T		intron	N/A	ENSP00000265436.7
	FOXP2	ENST00000408937.7	TSL:1	c.169-26891C>T		intron	N/A	ENSP00000386200.3
	FOXP2	ENST00000390668.3	TSL:1	c.166-26891C>T		intron	N/A	ENSP00000375084.3

Frequencies

GnomAD3 genomes AF: 0.0872 AC: 13242 AN: 151774 Hom.: 1196 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0704

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

GnomAD4 genome AF: 0.0874 AC: 13275 AN: 151892 Hom.: 1202 Cov.: 32 AF XY: 0.0876 AC XY: 6502 AN XY: 74256

African (AFR) AF: 0.228 AC: 9455 AN: 41436

American (AMR) AF: 0.0645 AC: 981 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 184 AN: 3468

East Asian (EAS) AF: 0.155 AC: 801 AN: 5158

South Asian (SAS) AF: 0.117 AC: 565 AN: 4820

European-Finnish (FIN) AF: 0.0158 AC: 167 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0141 AC: 954 AN: 67872

Other (OTH) AF: 0.0711 AC: 150 AN: 2110

Alfa AF: 0.0419 Hom.: 100

Bravo AF: 0.0996

Asia WGS AF: 0.135 AC: 470 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.39
PhyloP100		0.55
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: rs58552483; hg19: chr7-114147781;