rs797045587

chr7-114628563-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_014491.4(FOXP2):c.282G>T(p.Met94Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXP2 NM_014491.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 10.0

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
• BP6: Variant 7-114628563-G-T is Benign according to our data. Variant chr7-114628563-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 211044.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP2	NM_014491.4	c.282G>T	p.Met94Ile	missense_variant	4/17	ENST00000350908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP2	ENST00000350908.9	c.282G>T	p.Met94Ile	missense_variant	4/17	1	NM_014491.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 15, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.083	T;T;.;D;.;T;.;D;T;.;.;T;.;.;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
Sift4G	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.97, 0.53, 0.89, 0.66	.;.;.;D;.;P;P;D;.;.;.;.;P;.;P
Vest4		0.73
MutPred		0.21		Gain of catalytic residue at P96 (P = 0.0327);Gain of catalytic residue at P96 (P = 0.0327);Gain of catalytic residue at P96 (P = 0.0327);Gain of catalytic residue at P96 (P = 0.0327);Gain of catalytic residue at P96 (P = 0.0327);.;.;Gain of catalytic residue at P96 (P = 0.0327);Gain of catalytic residue at P96 (P = 0.0327);Gain of catalytic residue at P96 (P = 0.0327);.;Gain of catalytic residue at P96 (P = 0.0327);Gain of catalytic residue at P96 (P = 0.0327);Gain of catalytic residue at P96 (P = 0.0327);.;
MVP		0.90
MPC		0.71
ClinPred		0.73	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797045587; hg19: chr7-114268618;