7-114420421-A-T

Variant names:

• chr7-114420421-A-T
• rs1852469
• NM_014491.4:c.-11+5061A>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.-11+5061A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0574 in 152,006 control chromosomes in the GnomAD database, including 635 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 0.057 (635 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32
• Publications: 5 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=-0.54).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NM_014491.4	c.-11+5061A>T		intron_variant	Intron 1 of 16	ENST00000350908.9	NP_055306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000350908.9	c.-11+5061A>T		intron_variant	Intron 1 of 16	1	NM_014491.4	ENSP00000265436.7

Frequencies

GnomAD3 genomes AF: 0.0574 AC: 8712 AN: 151886 Hom.: 633 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0708

Gnomad ASJ AF: 0.0508

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0473

Gnomad OTH AF: 0.0632

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

GnomAD4 genome AF: 0.0574 AC: 8718 AN: 152006 Hom.: 635 Cov.: 32 AF XY: 0.0625 AC XY: 4644 AN XY: 74296

African (AFR) AF: 0.0134 AC: 557 AN: 41536

American (AMR) AF: 0.0712 AC: 1084 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.0508 AC: 176 AN: 3464

East Asian (EAS) AF: 0.365 AC: 1870 AN: 5128

South Asian (SAS) AF: 0.120 AC: 579 AN: 4820

European-Finnish (FIN) AF: 0.103 AC: 1091 AN: 10604

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0473 AC: 3210 AN: 67910

Other (OTH) AF: 0.0626 AC: 132 AN: 2110

Alfa AF: 0.0534 Hom.: 47

Bravo AF: 0.0533

Asia WGS AF: 0.215 AC: 745 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.88
PhyloP100		3.3
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: rs1852469; hg19: chr7-114060476;