chr7-114426635-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_014491.4(FOXP2):āc.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
NM_014491.4 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 3.67
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]
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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 |
---|---|---|---|---|---|---|---|---|
FOXP2 | NM_014491.4 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
FOXP2 | ENST00000350908.9 | c.124T>C | p.Ser42Pro | missense_variant | 2/17 | 1 | NM_014491.4 | ENSP00000265436 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151682Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249454Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134780
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459718Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726178
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GnomAD4 genome AF: 0.00000659 AC: 1AN: 151682Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74048
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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 submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T;.;.;.;T;T;T;.;T;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;.;N;.;N;N;N;.;.;N;.;N;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
.;.;.;N;D;N;N;N;N;N;N;.;N;N;N
REVEL
Benign
Sift
Benign
.;.;.;T;D;T;D;T;T;D;T;.;T;D;D
Sift4G
Benign
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
MutPred
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
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at