7-114426636-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014491.4(FOXP2):c.125C>G(p.Ser42Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S42P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FOXP2 NM_014491.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.03

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
• PP2: Missense variant where missense usually causes diseases, FOXP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.25906688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP2	NM_014491.4	c.125C>G	p.Ser42Cys	missense_variant	2/17	ENST00000350908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP2	ENST00000350908.9	c.125C>G	p.Ser42Cys	missense_variant	2/17	1	NM_014491.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249442 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459680 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FOXP2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2023

The FOXP2 c.125C>G variant is predicted to result in the amino acid substitution p.Ser42Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-114066691-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2018

The p.S42C variant (also known as c.125C>G), located in coding exon 1 of the FOXP2 gene, results from a C to G substitution at nucleotide position 125. The serine at codon 42 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Benign	0.11
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	30
Dann	Uncertain	0.98
DEOGEN2	Benign	0.097	T;T;.;D;.;.;.;D;T;T;.;T;.;.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.67	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
Sift4G	Uncertain	0.056	T;T;D;T;T;D;D;T;D;D;T;T;T;T;T
Polyphen		0.99, 1.0, 0.73, 0.51	.;.;.;D;.;.;D;D;.;.;.;.;P;.;P
Vest4		0.44
MutPred		0.12		Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);Loss of phosphorylation at S42 (P = 0.0205);.;
MVP		0.69
MPC		0.68
ClinPred		0.88	D
GERP RS		4.3
Varity_R		0.28
gMVP		0.40

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: rs754271344; hg19: chr7-114066691;