chr7-114600061-T-A

Variant names:

• chr7-114600061-T-A
• rs12531289
• NM_014491.4:c.259-28479T>A

Variant summary

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

The NM_014491.4(FOXP2):​c.259-28479T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.735 in 151,936 control chromosomes in the GnomAD database, including 44,319 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 0.73 (44319 hom., cov: 30)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.102
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.878 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.259-28479T>A		intron	N/A	NP_055306.1
	FOXP2	NM_148898.4		c.334-28479T>A		intron	N/A	NP_683696.2
	FOXP2	NM_148900.4		c.259-28479T>A		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.259-28479T>A		intron	N/A	ENSP00000265436.7
	FOXP2	ENST00000408937.7	TSL:1	c.334-28479T>A		intron	N/A	ENSP00000386200.3
	FOXP2	ENST00000390668.3	TSL:1	c.331-28479T>A		intron	N/A	ENSP00000375084.3

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111633 AN: 151818 Hom.: 44314 Cov.: 30

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.969

Gnomad AMR AF: 0.829

Gnomad ASJ AF: 0.793

Gnomad EAS AF: 0.765

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.868

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.884

Gnomad OTH AF: 0.761

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

GnomAD4 genome AF: 0.735 AC: 111669 AN: 151936 Hom.: 44319 Cov.: 30 AF XY: 0.738 AC XY: 54787 AN XY: 74226

African (AFR) AF: 0.405 AC: 16752 AN: 41392

American (AMR) AF: 0.829 AC: 12643 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.793 AC: 2752 AN: 3470

East Asian (EAS) AF: 0.764 AC: 3932 AN: 5144

South Asian (SAS) AF: 0.751 AC: 3618 AN: 4816

European-Finnish (FIN) AF: 0.868 AC: 9180 AN: 10578

Middle Eastern (MID) AF: 0.750 AC: 219 AN: 292

European-Non Finnish (NFE) AF: 0.884 AC: 60081 AN: 67980

Other (OTH) AF: 0.762 AC: 1610 AN: 2112

Alfa AF: 0.799 Hom.: 6309

Bravo AF: 0.716

Asia WGS AF: 0.747 AC: 2598 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.1
DANN	Benign	0.80
PhyloP100		-0.10
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: rs12531289; hg19: chr7-114240116;