chr7-114656047-T-C

Variant names:

• chr7-114656047-T-C
• rs1456031
• NM_014491.4:c.1267-2019T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_014491.4(FOXP2):​c.1267-2019T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 152,070 control chromosomes in the GnomAD database, including 15,899 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 0.44 (15899 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88
• Publications: 25 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

ENSG00000303050 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.541 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.1267-2019T>C		intron	N/A	NP_055306.1	O15409-1
	FOXP2	NM_148898.4		c.1342-2019T>C		intron	N/A	NP_683696.2	O15409-4
	FOXP2	NM_148900.4		c.1318-2019T>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.1267-2019T>C		intron	N/A	ENSP00000265436.7	O15409-1
	FOXP2	ENST00000408937.7	TSL:1	c.1342-2019T>C		intron	N/A	ENSP00000386200.3	O15409-4
	FOXP2	ENST00000393489.8	TSL:1	n.*1061-2019T>C		intron	N/A	ENSP00000377129.4	O15409-8

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67145 AN: 151952 Hom.: 15901 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.392

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

GnomAD4 genome AF: 0.442 AC: 67164 AN: 152070 Hom.: 15899 Cov.: 32 AF XY: 0.443 AC XY: 32910 AN XY: 74336

African (AFR) AF: 0.271 AC: 11254 AN: 41512

American (AMR) AF: 0.393 AC: 5990 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1300 AN: 3468

East Asian (EAS) AF: 0.497 AC: 2568 AN: 5170

South Asian (SAS) AF: 0.559 AC: 2690 AN: 4816

European-Finnish (FIN) AF: 0.555 AC: 5870 AN: 10586

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.532 AC: 36140 AN: 67954

Other (OTH) AF: 0.392 AC: 827 AN: 2108

Alfa AF: 0.456 Hom.: 2551

Bravo AF: 0.420

Asia WGS AF: 0.503 AC: 1747 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.80
PhyloP100		1.9
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: rs1456031; hg19: chr7-114296102; COSMIC: COSV63483042; COSMIC: COSV63483042;