NM_014491.4:c.258+36053T>C

Variant names:

• chr7-114570759-T-C
• rs17137124
• NM_014491.4:c.258+36053T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.853
• Publications: 21 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1231050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	NM_014491.4	MANE Select	c.258+36053T>C		intron	N/A	NP_055306.1	O15409-1
	FOXP2	NM_148898.4		c.259-48T>C		intron	N/A	NP_683696.2	O15409-4
	FOXP2	NM_148900.4		c.258+36053T>C		intron	N/A	NP_683698.2	O15409-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	ENST00000350908.9	TSL:1 MANE Select	c.258+36053T>C		intron	N/A	ENSP00000265436.7	O15409-1
	FOXP2	ENST00000408937.7	TSL:1	c.259-48T>C		intron	N/A	ENSP00000386200.3	O15409-4
	FOXP2	ENST00000390668.3	TSL:1	c.256-48T>C		intron	N/A	ENSP00000375084.3	Q8N6B5

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

GnomAD2 exomes AF: 0.560 AC: 138812 AN: 247724 AF XY: 0.558

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 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

African (AFR) AF: 0.309 AC: 9069 AN: 29360

American (AMR) AF: 0.668 AC: 29575 AN: 44246

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 9832 AN: 24748

East Asian (EAS) AF: 0.742 AC: 28664 AN: 38642

South Asian (SAS) AF: 0.603 AC: 49664 AN: 82300

European-Finnish (FIN) AF: 0.544 AC: 28933 AN: 53204

Middle Eastern (MID) AF: 0.390 AC: 2083 AN: 5342

European-Non Finnish (NFE) AF: 0.554 AC: 514157 AN: 928396

Other (OTH) AF: 0.545 AC: 29211 AN: 53594

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

African (AFR) AF: 0.323 AC: 13356 AN: 41414

American (AMR) AF: 0.590 AC: 8958 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1328 AN: 3460

East Asian (EAS) AF: 0.746 AC: 3851 AN: 5160

South Asian (SAS) AF: 0.604 AC: 2908 AN: 4818

European-Finnish (FIN) AF: 0.531 AC: 5598 AN: 10542

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36675 AN: 67736

Other (OTH) AF: 0.478 AC: 1005 AN: 2104

Alfa AF: 0.509 Hom.: 14326

Bravo AF: 0.485

Asia WGS AF: 0.646 AC: 2247 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.76
PhyloP100		0.85
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: rs17137124; hg19: chr7-114210814; COSMIC: COSV63482433;