rs139649711

chr7-114654017-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000390668.3(FOXP2):c.1346C>T(p.Ala449Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,613,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: FOXP2 ENST00000390668.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.57

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 7-114654017-C-T is Benign according to our data. Variant chr7-114654017-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000289 (44/152260) while in subpopulation NFE AF= 0.000471 (32/68012). AF 95% confidence interval is 0.000342. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP2	NM_014491.4	c.1266+8C>T		splice_region_variant, intron_variant		ENST00000350908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP2	ENST00000350908.9	c.1266+8C>T		splice_region_variant, intron_variant		1	NM_014491.4	P1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 251202 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135750

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000253 AC: 369 AN: 1460922 Hom.: 0 Cov.: 31 AF XY: 0.000241 AC XY: 175 AN XY: 726822

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000319

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74430

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000306 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Childhood apraxia of speech Benign:2

Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 08, 2019	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Oct 07, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.36	T;T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	0.64	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.015	D;T
Sift4G	Benign	0.46	T;T
Polyphen		1.0	D;D
Vest4		0.75
MVP		0.53
ClinPred		0.089	T
GERP RS		6.2

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

LitVar

Other links and lift over

dbSNP: rs139649711; hg19: chr7-114294072;