7-114415272-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014491.4(FOXP2):c.-99G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00298 in 453,722 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (6 hom.)
• Consequence: FOXP2 NM_014491.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.61

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 7-114415272-G-A is Benign according to our data. Variant chr7-114415272-G-A is described in ClinVar as [Benign]. Clinvar id is 358599.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00719 (1093/152040) while in subpopulation AFR AF= 0.0249 (1032/41482). AF 95% confidence interval is 0.0236. There are 14 homozygotes in gnomad4. There are 528 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1092 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP2	NM_014491.4	c.-99G>A		5_prime_UTR_variant	1/17	ENST00000350908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP2	ENST00000350908.9	c.-99G>A		5_prime_UTR_variant	1/17	1	NM_014491.4	P1
	ENST00000415146.1	n.42-488C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1092 AN: 151922 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00151 AC: 196 AN: 129914 Hom.: 6 AF XY: 0.00111 AC XY: 79 AN XY: 71096

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.000986

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000447

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.000747

GnomAD4 exome AF: 0.000865 AC: 261 AN: 301682 Hom.: 6 Cov.: 0 AF XY: 0.000657 AC XY: 113 AN XY: 171940

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.000954

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000335

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.00135

GnomAD4 genome AF: 0.00719 AC: 1093 AN: 152040 Hom.: 14 Cov.: 32 AF XY: 0.00710 AC XY: 528 AN XY: 74330

Gnomad4 AFR AF: 0.0249

Gnomad4 AMR AF: 0.00269

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00299 Hom.: 5

Bravo AF: 0.00819

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Childhood apraxia of speech Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	14
Dann	Benign	0.87

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: rs116320717; hg19: chr7-114055327;