7-114629915-GCAACAACAACAA-GCAACAACAACAACAA

Variant names:

• chr7-114629915-G-GCAA
• rs398124272
• NM_014491.4:c.522_524dupACA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16
• Publications: 1 publications found

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

ACMG classification

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	NM_014491.4	MANE Select	c.522_524dupACA	p.Gln175dup	disruptive_inframe_insertion	Exon 5 of 17	NP_055306.1	O15409-1
	FOXP2	NM_148898.4		c.597_599dupACA	p.Gln200dup	disruptive_inframe_insertion	Exon 6 of 18	NP_683696.2	O15409-4
	FOXP2	NM_148900.4		c.573_575dupACA	p.Gln192dup	disruptive_inframe_insertion	Exon 6 of 18	NP_683698.2	O15409-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	ENST00000350908.9	TSL:1 MANE Select	c.522_524dupACA	p.Gln175dup	disruptive_inframe_insertion	Exon 5 of 17	ENSP00000265436.7	O15409-1
	FOXP2	ENST00000408937.7	TSL:1	c.597_599dupACA	p.Gln200dup	disruptive_inframe_insertion	Exon 6 of 18	ENSP00000386200.3	O15409-4
	FOXP2	ENST00000390668.3	TSL:1	c.594_596dupACA	p.Gln199dup	disruptive_inframe_insertion	Exon 5 of 10	ENSP00000375084.3	Q8N6B5

Frequencies

GnomAD3 genomes AF: 0.00000672 AC: 1 AN: 148770 Hom.: 0 Cov.: 33

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: 8 AN: 241892 AF XY: 0.0000381

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: 24 AN: 1459722 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 726150

African (AFR) AF: 0.000240 AC: 8 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86172

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110776

Other (OTH) AF: 0.0000663 AC: 4 AN: 60316

GnomAD4 genome AF: 0.00000672 AC: 1 AN: 148770 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 1 AN XY: 72424

African (AFR) AF: 0.00 AC: 0 AN: 40302

American (AMR) AF: 0.00 AC: 0 AN: 14644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67208

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2
Mutation Taster		=56/44	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs398124272; hg19: chr7-114269970;