Genetic Variant FOXP2:p.Gln175del (chr7-114629915-GCAA-G) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_014491.4(FOXP2):c.522_524delACA(p.Gln175del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00181 in 1,607,486 control chromosomes in the GnomAD database, including 26 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q174Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0025 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 22 hom. )

Consequence

FOXP2
NM_014491.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

FOXP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_014491.4

BP6

Variant 7-114629915-GCAA-G is Benign according to our data. Variant chr7-114629915-GCAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0025 (372/148884) while in subpopulation EAS AF = 0.0198 (101/5104). AF 95% confidence interval is 0.0167. There are 4 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 372 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXP2	NM_014491.4	MANE Select	c.522_524delACA	p.Gln175del	disruptive_inframe_deletion	Exon 5 of 17	NP_055306.1	O15409-1
FOXP2	NM_148898.4		c.597_599delACA	p.Gln200del	disruptive_inframe_deletion	Exon 6 of 18	NP_683696.2	O15409-4
FOXP2	NM_148900.4		c.573_575delACA	p.Gln192del	disruptive_inframe_deletion	Exon 6 of 18	NP_683698.2	O15409-9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXP2	ENST00000350908.9	TSL:1 MANE Select	c.522_524delACA	p.Gln175del	disruptive_inframe_deletion	Exon 5 of 17	ENSP00000265436.7	O15409-1
FOXP2	ENST00000408937.7	TSL:1	c.597_599delACA	p.Gln200del	disruptive_inframe_deletion	Exon 6 of 18	ENSP00000386200.3	O15409-4
FOXP2	ENST00000390668.3	TSL:1	c.594_596delACA	p.Gln199del	disruptive_inframe_deletion	Exon 5 of 10	ENSP00000375084.3	Q8N6B5

Frequencies

GnomAD3 genomes

AF:

0.00251

AC:

374

AN:

148768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00205

Gnomad ASJ

AF:

0.000587

Gnomad EAS

AF:

0.0201

Gnomad SAS

AF:

0.00192

Gnomad FIN

AF:

0.00966

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.000967

Gnomad OTH

AF:

0.00293

GnomAD2 exomes

AF:

0.00332

AC:

803

AN:

241892

AF XY:

0.00313

show subpopulations

Gnomad AFR exome

AF:

0.00180

Gnomad AMR exome

AF:

0.00395

Gnomad ASJ exome

AF:

0.00162

Gnomad EAS exome

AF:

0.0141

Gnomad FIN exome

AF:

0.00881

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.00383

GnomAD4 exome

AF:

0.00174

AC:

2531

AN:

1458602

Hom.:

AF XY:

0.00178

AC XY:

1289

AN XY:

725602

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

33328

American (AMR)

AF:

0.00374

AC:

167

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00219

AC:

AN:

26026

East Asian (EAS)

AF:

0.0264

AC:

1045

AN:

39616

South Asian (SAS)

AF:

0.00194

AC:

167

AN:

86130

European-Finnish (FIN)

AF:

0.00823

AC:

435

AN:

52882

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000426

AC:

473

AN:

1109964

Other (OTH)

AF:

0.00226

AC:

136

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

171

342

513

684

855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00250

AC:

372

AN:

148884

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

228

AN XY:

72548

show subpopulations

African (AFR)

AF:

0.00148

AC:

AN:

40424

American (AMR)

AF:

0.00205

AC:

AN:

14664

Ashkenazi Jewish (ASJ)

AF:

0.000587

AC:

AN:

3410

East Asian (EAS)

AF:

0.0198

AC:

101

AN:

5104

South Asian (SAS)

AF:

0.00192

AC:

AN:

4684

European-Finnish (FIN)

AF:

0.00966

AC:

AN:

10140

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000967

AC:

AN:

67200

Other (OTH)

AF:

0.00290

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00276

Hom.:

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Childhood apraxia of speech (2)

FOXP2-related disorder (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.2

Mutation Taster

=53/47

polymorphism

(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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7-114629915-GCAACAACAACAA-GCAACAACAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over