Variant chr7-114426635-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014491.4(FOXP2):c.124T>A(p.Ser42Thr) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXP2
NM_014491.4 missense

Scores

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]

FOXP2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13244072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP2	NM_014491.4 link	c.124T>A	p.Ser42Thr	missense_variant	2/17	ENST00000350908.9	NP_055306.1	O15409-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP2	ENST00000350908.9 link	c.124T>A	p.Ser42Thr	missense_variant	2/17	1	NM_014491.4	ENSP00000265436.7		O15409-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.85e-7

AC:

AN:

1459716

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.124T>A (p.S42T) alteration is located in exon 2 (coding exon 1) of the FOXP2 gene. This alteration results from a T to A substitution at nucleotide position 124, causing the serine (S) at amino acid position 42 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.079

T;T;.;T;.;.;.;T;T;T;.;T;.;.;T

Eigen

Benign

-0.015

Eigen_PC

Benign

0.067

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.79

T;T;T;.;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.13

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

MetaSVM

Uncertain

0.069

MutationAssessor

Benign

0.69

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

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.69

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

REVEL

Benign

0.13

Sift

Benign

0.17

.;.;.;T;T;T;T;T;T;T;T;.;T;T;T

Sift4G

Benign

0.37

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

Polyphen

0.94, 0.49, 0.0

.;.;.;P;.;.;P;P;.;.;.;.;B;.;B

Vest4

0.29

MutPred

0.090

Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);Gain of glycosylation at S41 (P = 0.043);.;

MVP

0.85

MPC

0.39

ClinPred

0.62

GERP RS

2.4

Varity_R

0.15

gMVP

0.32

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over