rs6961558

chr7-114087728-G-Achr7-114087728-G-Cchr7-114087728-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000440349.5(FOXP2):c.-247+1117G>A variant causes a intron, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0536 in 151,458 control chromosomes in the GnomAD database, including 499 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 0.054 (499 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXP2 ENST00000440349.5 intron, NMD_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450

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=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP2	NR_033766.2	n.285+1117G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP2	ENST00000440349.5	c.-247+1117G>A		intron_variant, NMD_transcript_variant		1
FOXP2	ENST00000703616.1	c.-357G>A		5_prime_UTR_variant	1/21
FOXP2	ENST00000703612.1	c.-247+1117G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0536 AC: 8119 AN: 151340 Hom.: 499 Cov.: 31

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.000974

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.00369

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0554

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 24 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 14

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0536 AC: 8124 AN: 151458 Hom.: 499 Cov.: 31 AF XY: 0.0520 AC XY: 3849 AN XY: 74064

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.0361

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.000977

Gnomad4 SAS AF: 0.0214

Gnomad4 FIN AF: 0.00369

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.0548

Alfa AF: 0.0169 Hom.: 34

Bravo AF: 0.0595

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	8.4
Dann	Benign	0.93

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6961558; hg19: chr7-113727783;