NM_014491.4:c.522_524delACA

Variant names:

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 95608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-114629915-GCAA-G is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 372 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP2	NM_014491.4 link	c.522_524delACA	p.Gln175del	disruptive_inframe_deletion	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_524delACA	p.Gln175del	disruptive_inframe_deletion	Exon 5 of 17	1	NM_014491.4	ENSP00000265436.7		O15409-1

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

GnomAD3 exomes

AF:

0.00332

AC:

803

AN:

241892

Hom.:

AF XY:

0.00313

AC XY:

410

AN XY:

131072

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 SAS exome

AF:

0.00195

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

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.00374

Gnomad4 ASJ exome

AF:

0.00219

Gnomad4 EAS exome

AF:

0.0264

Gnomad4 SAS exome

AF:

0.00194

Gnomad4 FIN exome

AF:

0.00823

Gnomad4 NFE exome

AF:

0.000426

Gnomad4 OTH exome

AF:

0.00226

GnomAD4 genome

AF:

0.00250

AC:

372

AN:

148884

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

228

AN XY:

72548

show subpopulations

Gnomad4 AFR

AF:

0.00148

Gnomad4 AMR

AF:

0.00205

Gnomad4 ASJ

AF:

0.000587

Gnomad4 EAS

AF:

0.0198

Gnomad4 SAS

AF:

0.00192

Gnomad4 FIN

AF:

0.00966

Gnomad4 NFE

AF:

0.000967

Gnomad4 OTH

AF:

0.00290

Alfa

AF:

0.00276

Hom.:

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Childhood apraxia of speech

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Aug 20, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FOXP2-related disorder

Benign:1

Dec 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Oct 20, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over