7-114654350-G-C

Variant names:

• chr7-114654350-G-C
• rs936146
• NM_014491.4:c.1266+341G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014491.4(FOXP2):​c.1266+341G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 151,858 control chromosomes in the GnomAD database, including 10,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.34 (10232 hom., cov: 32)
• Consequence: FOXP2 NM_014491.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.39
• Publications: 14 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)

ENSG00000303050 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 7-114654350-G-C is Benign according to our data. Variant chr7-114654350-G-C is described in ClinVar as Benign. ClinVar VariationId is 1220788.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NM_014491.4	c.1266+341G>C		intron_variant	Intron 10 of 16	ENST00000350908.9	NP_055306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000350908.9	c.1266+341G>C		intron_variant	Intron 10 of 16	1	NM_014491.4	ENSP00000265436.7

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52158 AN: 151740 Hom.: 10236 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.320

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

GnomAD4 genome AF: 0.343 AC: 52163 AN: 151858 Hom.: 10232 Cov.: 32 AF XY: 0.340 AC XY: 25203 AN XY: 74204

African (AFR) AF: 0.176 AC: 7281 AN: 41462

American (AMR) AF: 0.312 AC: 4764 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 993 AN: 3462

East Asian (EAS) AF: 0.143 AC: 736 AN: 5156

South Asian (SAS) AF: 0.314 AC: 1512 AN: 4822

European-Finnish (FIN) AF: 0.458 AC: 4820 AN: 10514

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30979 AN: 67892

Other (OTH) AF: 0.318 AC: 668 AN: 2100

Alfa AF: 0.274 Hom.: 812

Bravo AF: 0.324

Asia WGS AF: 0.226 AC: 788 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.73
PhyloP100		1.4
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: rs936146; hg19: chr7-114294405;