7-114629915-GCAA-G

Position:

• chr7-114629915-GCAA-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The ENST00000350908.9(FOXP2):​c.522_524del​(p.Gln191del) variant causes a 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 ENST00000350908.9 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.16

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000350908.9
• 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/exons	MANE	Protein	UniProt
FOXP2	NM_014491.4	c.522_524del	p.Gln191del	inframe_deletion	5/17	ENST00000350908.9	NP_055306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000350908.9	c.522_524del	p.Gln191del	inframe_deletion	5/17	1	NM_014491.4	ENSP00000265436	P1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 374 AN: 148768 Hom.: 5 Cov.: 33

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.: 4 AF XY: 0.00313 AC XY: 410 AN XY: 131072

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.: 22 AF XY: 0.00178 AC XY: 1289 AN XY: 725602

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.: 4 Cov.: 33 AF XY: 0.00314 AC XY: 228 AN XY: 72548

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.: 0

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Childhood apraxia of speech Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 20, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 20, 2013

- -

FOXP2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs398124272; hg19: chr7-114269970;