chr7-114426635-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_014491.4(FOXP2):ā€‹c.124T>Cā€‹(p.Ser42Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,400 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 (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

FOXP2
NM_014491.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67
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]

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=0.14944565).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FOXP2NM_014491.4 linkuse as main transcriptc.124T>C p.Ser42Pro missense_variant 2/17 ENST00000350908.9 NP_055306.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FOXP2ENST00000350908.9 linkuse as main transcriptc.124T>C p.Ser42Pro missense_variant 2/171 NM_014491.4 ENSP00000265436 P1O15409-1

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151682
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249454
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134780
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000891
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459718
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726178
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151682
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74048
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Childhood apraxia of speech Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.030
T;T;.;T;.;.;.;T;T;T;.;T;.;.;T
Eigen
Benign
0.14
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.94
D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.061
D
MetaRNN
Benign
0.15
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.34
D
MutationAssessor
Benign
0.34
.;.;.;N;.;N;N;N;.;.;N;.;N;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-0.91
.;.;.;N;D;N;N;N;N;N;N;.;N;N;N
REVEL
Benign
0.15
Sift
Benign
0.073
.;.;.;T;D;T;D;T;T;D;T;.;T;D;D
Sift4G
Benign
0.15
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.97, 0.99, 0.43, 0.23
.;.;.;D;.;.;D;D;.;.;.;.;B;.;B
Vest4
0.51
MutPred
0.079
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
0.84
MPC
0.33
ClinPred
0.64
D
GERP RS
2.4
Varity_R
0.33
gMVP
0.42

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.

Other links and lift over

dbSNP: rs942638508; hg19: chr7-114066690; API