rs17508329

Positions:

• chr7-114159110-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000440349.5(FOXP2):​c.-246-3834A>C variant causes a intron, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 152,250 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.011 (8 hom., cov: 32)
• Consequence: FOXP2 ENST00000440349.5 intron, NMD_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.32

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0113 (1728/152250) while in subpopulation NFE AF= 0.0169 (1150/68000). AF 95% confidence interval is 0.0161. There are 8 homozygotes in gnomad4. There are 829 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1728 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP2	NR_033766.2	n.285+72499A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP2	ENST00000440349.5	c.-246-3834A>C		intron_variant, NMD_transcript_variant		1
FOXP2	ENST00000635638.1	c.-246-3834A>C		intron_variant		5
FOXP2	ENST00000703612.1	c.-246-3834A>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1728 AN: 152132 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0134

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0113 AC: 1728 AN: 152250 Hom.: 8 Cov.: 32 AF XY: 0.0111 AC XY: 829 AN XY: 74438

Gnomad4 AFR AF: 0.00272

Gnomad4 AMR AF: 0.0166

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.0169

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0137 Hom.: 2

Bravo AF: 0.0114

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.63

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17508329; hg19: chr7-113799165;