chr7-114426561-A-T

Variant names:

• chr7-114426561-A-T
• rs201649896
• NM_014491.4:c.50A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014491.4(FOXP2):​c.50A>T​(p.Gln17Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,611,446 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: FOXP2 NM_014491.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:1
• Conservation: PhyloP100: 8.87
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06398103).
• BP6: Variant 7-114426561-A-T is Benign according to our data. Variant chr7-114426561-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195296.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000303 (46/151668) while in subpopulation NFE AF = 0.000502 (34/67788). AF 95% confidence interval is 0.000369. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 46 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	NM_014491.4	MANE Select	c.50A>T	p.Gln17Leu	missense	Exon 2 of 17	NP_055306.1	O15409-1
	FOXP2	NM_148898.4		c.50A>T	p.Gln17Leu	missense	Exon 2 of 18	NP_683696.2	O15409-4
	FOXP2	NM_148900.4		c.50A>T	p.Gln17Leu	missense	Exon 2 of 18	NP_683698.2	O15409-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP2	ENST00000350908.9	TSL:1 MANE Select	c.50A>T	p.Gln17Leu	missense	Exon 2 of 17	ENSP00000265436.7	O15409-1
	FOXP2	ENST00000408937.7	TSL:1	c.50A>T	p.Gln17Leu	missense	Exon 2 of 18	ENSP00000386200.3	O15409-4
	FOXP2	ENST00000390668.3	TSL:1	c.47A>T	p.Gln16Leu	missense	Exon 1 of 10	ENSP00000375084.3	Q8N6B5

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 151668 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000502

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000428 AC: 107 AN: 249876 AF XY: 0.000385

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00289

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.000515

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000314 AC: 459 AN: 1459778 Hom.: 2 Cov.: 31 AF XY: 0.000315 AC XY: 229 AN XY: 726188

African (AFR) AF: 0.0000300 AC: 1 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 75 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.000693 AC: 37 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000280 AC: 311 AN: 1110554

Other (OTH) AF: 0.000581 AC: 35 AN: 60240

GnomAD4 genome AF: 0.000303 AC: 46 AN: 151668 Hom.: 0 Cov.: 32 AF XY: 0.000297 AC XY: 22 AN XY: 74050

African (AFR) AF: 0.0000725 AC: 3 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000502 AC: 34 AN: 67788

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000524 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000546

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Childhood apraxia of speech (2)
-	-	1	FOXP2-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.064	T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.3	L
PhyloP100		8.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.72
MVP		0.78
MPC		0.62
ClinPred		0.12	T
GERP RS		5.4
PromoterAI		-0.019	Neutral
Varity_R		0.49
gMVP		0.48
Mutation Taster		=222/78	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: rs201649896; hg19: chr7-114066616; COSMIC: COSV104416955;