7-114642616-C-G

Variant names:

• chr7-114642616-C-G
• rs121908378
• NM_014491.4:c.982C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014491.4(FOXP2):​c.982C>G​(p.Arg328Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R328Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FOXP2 NM_014491.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• specific language disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood apraxia of speech

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000303050 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21737027).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014491.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	NM_014491.4	MANE Select	c.982C>G	p.Arg328Gly	missense	Exon 7 of 17	NP_055306.1
	FOXP2	NM_148898.4		c.1057C>G	p.Arg353Gly	missense	Exon 8 of 18	NP_683696.2
	FOXP2	NM_148900.4		c.1033C>G	p.Arg345Gly	missense	Exon 8 of 18	NP_683698.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	ENST00000350908.9	TSL:1 MANE Select	c.982C>G	p.Arg328Gly	missense	Exon 7 of 17	ENSP00000265436.7
	FOXP2	ENST00000408937.7	TSL:1	c.1057C>G	p.Arg353Gly	missense	Exon 8 of 18	ENSP00000386200.3
	FOXP2	ENST00000390668.3	TSL:1	c.1054C>G	p.Arg352Gly	missense	Exon 7 of 10	ENSP00000375084.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460364 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726616

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110740

Other (OTH) AF: 0.0000166 AC: 1 AN: 60332

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.0058	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.17
Sift	Uncertain	0.012	D
Sift4G	Benign	0.34	T
Polyphen		0.92	P
Vest4		0.63
MutPred		0.21		Loss of stability (P = 0.0086)
MVP		0.56
MPC		0.21
ClinPred		0.96	D
GERP RS		1.1
Varity_R		0.26
gMVP		0.42
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs121908378; hg19: chr7-114282671;