rs1553663140

chr3-70972669-A-Gchr3-70972669-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001349338.3(FOXP1):c.1538T>C(p.Val513Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.32

Genes affected

FOXP1 (HGNC:3823): (forkhead box P1) This gene belongs to subfamily P of the forkhead box (FOX) transcription factor family. Forkhead box transcription factors play important roles in the regulation of tissue- and cell type-specific gene transcription during both development and adulthood. Forkhead box P1 protein contains both DNA-binding- and protein-protein binding-domains. This gene may act as a tumor suppressor as it is lost in several tumor types and maps to a chromosomal region (3p14.1) reported to contain a tumor suppressor gene(s). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001349338.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP1	NM_001349338.3	c.1538T>C	p.Val513Ala	missense_variant	18/21	ENST00000649528.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP1	ENST00000649528.3	c.1538T>C	p.Val513Ala	missense_variant	18/21		NM_001349338.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2017

- -

Intellectual disability-severe speech delay-mild dysmorphism syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 12, 2018

The FOXP1 c.1538T>C p.(Val513Ala) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. The variant is located in the FOX domain of the gene. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the evidence, the c.1538T>C p.(Val513Ala) variant is classified as a variant of uncertain significance for intellectual developmental disorder with language impairment with or without autistic features. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;.;D;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;.;H;.;.;.;.;.;.;H;.;.;.;.;H;.;.;H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;.;D;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.91
MutPred		0.80		Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);.;Gain of disorder (P = 0.0319);.;.;.;.;.;.;Gain of disorder (P = 0.0319);.;.;.;.;Gain of disorder (P = 0.0319);.;.;Gain of disorder (P = 0.0319);.;.;.;Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);
MVP		0.94
MPC		3.3
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74

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: rs1553663140; hg19: chr3-71021820;