7-114416000-G-C

Variant names:

• chr7-114416000-G-C
• rs12533005
• NM_014491.4:c.-11+640G>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.-11+640G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 151,816 control chromosomes in the GnomAD database, including 11,767 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 0.37 (11767 hom., cov: 31)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000224595 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.609 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+640G>C		intron	N/A	NP_055306.1
	FOXP2	NM_148898.4		c.-11+640G>C		intron	N/A	NP_683696.2
	FOXP2	NM_148900.4		c.-11+640G>C		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+640G>C		intron	N/A	ENSP00000265436.7
	FOXP2	ENST00000408937.7	TSL:1	c.-11+640G>C		intron	N/A	ENSP00000386200.3
	FOXP2	ENST00000378237.7	TSL:1	c.-11+640G>C		intron	N/A	ENSP00000367482.3

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55730 AN: 151696 Hom.: 11771 Cov.: 31

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.405

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

GnomAD4 genome AF: 0.367 AC: 55731 AN: 151816 Hom.: 11767 Cov.: 31 AF XY: 0.373 AC XY: 27653 AN XY: 74182

African (AFR) AF: 0.154 AC: 6363 AN: 41440

American (AMR) AF: 0.380 AC: 5784 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1781 AN: 3472

East Asian (EAS) AF: 0.627 AC: 3222 AN: 5138

South Asian (SAS) AF: 0.419 AC: 2019 AN: 4822

European-Finnish (FIN) AF: 0.491 AC: 5183 AN: 10552

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 29911 AN: 67872

Other (OTH) AF: 0.406 AC: 856 AN: 2110

Alfa AF: 0.284 Hom.: 835

Bravo AF: 0.353

Asia WGS AF: 0.504 AC: 1751 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		1.3
PromoterAI		-0.0065	Neutral
Mutation Taster		=99/1	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: rs12533005; hg19: chr7-114056055;