Genetic Variant FOXP2:p.Gln175dup (chr7-114629915-G-GCAA) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_014491.4(FOXP2):c.522_524dupACA(p.Gln175dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000155 in 1,608,492 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q175Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

FOXP2
NM_014491.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.16

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_014491.4

BS2

High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NM_014491.4 link	c.522_524dupACA	p.Gln175dup	disruptive_inframe_insertion	Exon 5 of 17	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.522_524dupACA	p.Gln175dup	disruptive_inframe_insertion	Exon 5 of 17	1	NM_014491.4	ENSP00000265436.7		O15409-1

Frequencies

GnomAD3 genomes

AF:

0.00000672

AC:

AN:

148770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000331

AC:

AN:

241892

AF XY:

0.0000381

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000279

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1459722

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726150

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

33358

American (AMR)

AF:

0.00

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26040

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

53020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1110776

Other (OTH)

AF:

0.0000663

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000672

AC:

AN:

148770

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40302

American (AMR)

AF:

0.00

AC:

AN:

14644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.000195

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67208

Other (OTH)

AF:

0.00

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.2

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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7-114629915-GCAACAACAACAA-GCAACAACAACAACAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over