7-114570759-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014491.4(FOXP2):c.258+36053T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,411,456 control chromosomes in the GnomAD database, including 218,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (19284 hom., cov: 32)
  • Exomes 𝑓: 0.56 (198739 hom.)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.853

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-114570759-T-C is Benign according to our data. Variant chr7-114570759-T-C is described in ClinVar as [Benign]. Clinvar id is 1231050.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP2	NM_014491.4	c.258+36053T>C		intron_variant		ENST00000350908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP2	ENST00000350908.9	c.258+36053T>C		intron_variant		1	NM_014491.4	P1

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74259 AN: 151506 Hom.: 19277 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.476

GnomAD3 exomes AF: 0.560 AC: 138812 AN: 247724 Hom.: 40396 AF XY: 0.558 AC XY: 75090 AN XY: 134472

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.678

Gnomad ASJ exome AF: 0.396

Gnomad EAS exome AF: 0.730

Gnomad SAS exome AF: 0.603

Gnomad FIN exome AF: 0.541

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.527

GnomAD4 exome AF: 0.557 AC: 701188 AN: 1259832 Hom.: 198739 Cov.: 18 AF XY: 0.556 AC XY: 354464 AN XY: 637650

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.668

Gnomad4 ASJ exome AF: 0.397

Gnomad4 EAS exome AF: 0.742

Gnomad4 SAS exome AF: 0.603

Gnomad4 FIN exome AF: 0.544

Gnomad4 NFE exome AF: 0.554

Gnomad4 OTH exome AF: 0.545

GnomAD4 genome AF: 0.490 AC: 74291 AN: 151624 Hom.: 19284 Cov.: 32 AF XY: 0.494 AC XY: 36634 AN XY: 74106

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.590

Gnomad4 ASJ AF: 0.384

Gnomad4 EAS AF: 0.746

Gnomad4 SAS AF: 0.604

Gnomad4 FIN AF: 0.531

Gnomad4 NFE AF: 0.541

Gnomad4 OTH AF: 0.478

Alfa AF: 0.506 Hom.: 9205

Bravo AF: 0.485

Asia WGS AF: 0.646 AC: 2247 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	7.2
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs17137124; hg19: chr7-114210814; COSMIC: COSV63482433;