7-114426600-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014491.4(FOXP2):c.89G>A(p.Gly30Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXP2 NM_014491.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FOXP2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP2	NM_014491.4	c.89G>A	p.Gly30Asp	missense_variant	2/17	ENST00000350908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP2	ENST00000350908.9	c.89G>A	p.Gly30Asp	missense_variant	2/17	1	NM_014491.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2018

The p.G30D variant (also known as c.89G>A), located in coding exon 1 of the FOXP2 gene, results from a G to A substitution at nucleotide position 89. The glycine at codon 30 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.041	T;T;.;D;.;.;.;D;T;T;.;T;.;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;T;T;D;T;T;T
Polyphen		0.99, 1.0, 0.85	.;.;.;D;.;.;D;D;.;.;.;.;D;.;P
Vest4		0.85
MutPred		0.19		Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);.;
MVP		0.84
MPC		0.75
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.66
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-114066655;