dbSNP rs1456031: FOXP2:c.1267-2019T>C (chr7-114656047-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.88

Publications

25 publications found

Variant links:

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)

FOXP2 links:

ENSG00000303050 (HGNC:):

ENSG00000303050 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NM_014491.4 link	c.1267-2019T>C		intron_variant	Intron 10 of 16	ENST00000350908.9	NP_055306.1	O15409-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000350908.9 link	c.1267-2019T>C		intron_variant	Intron 10 of 16	1	NM_014491.4	ENSP00000265436.7		O15409-1

Frequencies

GnomAD3 genomes

AF:

0.442

AC:

67145

AN:

151952

Hom.:

15901

Cov.:

show subpopulations

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.:

AF XY:

0.443

AC XY:

32910

AN XY:

74336

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.532

AC:

36140

AN:

67954

Other (OTH)

AF:

0.392

AC:

827

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1821

3643

5464

7286

9107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

644

1288

1932

2576

3220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over