7-114420608-A-T

Variant names:

• chr7-114420608-A-T
• rs10228350
• NM_014491.4:c.-11+5248A>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+5248A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 151,768 control chromosomes in the GnomAD database, including 7,661 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 0.29 (7661 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.361
• Publications: 9 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=-0.6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 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.-11+5248A>T		intron	N/A	NP_055306.1
	FOXP2	NM_148898.4		c.-11+5248A>T		intron	N/A	NP_683696.2
	FOXP2	NM_148900.4		c.-11+5248A>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.-11+5248A>T		intron	N/A	ENSP00000265436.7
	FOXP2	ENST00000408937.7	TSL:1	c.-11+5248A>T		intron	N/A	ENSP00000386200.3
	FOXP2	ENST00000378237.7	TSL:1	c.-11+5248A>T		intron	N/A	ENSP00000367482.3

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44271 AN: 151650 Hom.: 7661 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0514

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.275

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

GnomAD4 genome AF: 0.292 AC: 44278 AN: 151768 Hom.: 7661 Cov.: 32 AF XY: 0.285 AC XY: 21110 AN XY: 74158

African (AFR) AF: 0.148 AC: 6120 AN: 41450

American (AMR) AF: 0.264 AC: 4020 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 762 AN: 3454

East Asian (EAS) AF: 0.0506 AC: 260 AN: 5140

South Asian (SAS) AF: 0.227 AC: 1095 AN: 4820

European-Finnish (FIN) AF: 0.369 AC: 3895 AN: 10556

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27200 AN: 67836

Other (OTH) AF: 0.275 AC: 579 AN: 2104

Alfa AF: 0.211 Hom.: 520

Bravo AF: 0.279

Asia WGS AF: 0.154 AC: 537 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.7
DANN	Benign	0.89
PhyloP100		-0.36
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: rs10228350; hg19: chr7-114060663;