7-114426636-C-G

Position:

chr7-114426636-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.03

Variant links:

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]

FOXP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FOXP2. . Gene score misZ 1.8963 (greater than the threshold 3.09). Trascript score misZ 3.108 (greater than threshold 3.09). GenCC has associacion of gene with childhood apraxia of speech, specific language disorder.

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 linkuse as main transcript	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 linkuse as main transcript	c.125C>G	p.Ser42Cys	missense_variant	2/17	1	NM_014491.4	P1	O15409-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249442

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134768

show subpopulations

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:

AN:

1459680

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726156

show subpopulations

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

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

LIST_S2

Uncertain

0.95

D;D;D;.;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.078

MetaRNN

Benign

0.26

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

0.69

.;.;.;N;.;N;N;N;.;.;N;.;N;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.5

.;.;.;N;D;N;N;N;N;N;N;.;N;N;N

REVEL

Benign

0.090

Sift

Uncertain

0.021

.;.;.;D;D;D;D;D;D;D;D;.;D;D;D

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over