7-114426630-C-G

Position:

• chr7-114426630-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014491.4(FOXP2):​c.119C>G​(p.Thr40Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 5.79

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.347808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP2	NM_014491.4	c.119C>G	p.Thr40Ser	missense_variant	2/17	ENST00000350908.9	NP_055306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000350908.9	c.119C>G	p.Thr40Ser	missense_variant	2/17	1	NM_014491.4	ENSP00000265436.7

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;.;T;.;.;.;T;T;T;.;T;.;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T;.;T;T;T;T;T;T;T;T;T;D;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.26	.;.;.;N;.;N;N;N;.;.;N;.;N;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.75	.;.;.;N;D;N;N;N;N;N;N;.;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.34	.;.;.;T;T;T;T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.74	T;T;T;T;D;T;T;T;T;T;T;T;T;T;T
Polyphen		0.89, 0.99, 0.97	.;.;.;P;.;.;D;P;.;.;.;.;D;.;D
Vest4		0.42
MutPred		0.22		Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);Gain of phosphorylation at S45 (P = 0.2004);.;
MVP		0.75
MPC		0.59
ClinPred		0.65	D
GERP RS		5.3
Varity_R		0.31
gMVP		0.27

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: chr7-114066685;