rs1057518926

Positions:

• chr3-70977675-G-C
• chr3-70977675-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001349338.3(FOXP1):​c.1396C>G​(p.Pro466Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P466T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_001349338.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-70977675-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1013484.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 3-70977675-G-C is Pathogenic according to our data. Variant chr3-70977675-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374144.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP1	NM_001349338.3	c.1396C>G	p.Pro466Ala	missense_variant	16/21	ENST00000649528.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP1	ENST00000649528.3	c.1396C>G	p.Pro466Ala	missense_variant	16/21		NM_001349338.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Strabismus;C0454644:Delayed speech and language development;C1851897:Anterior creases of earlobe;C1854408:Glabellar hemangioma;C3714756:Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 21, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D;D;D;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	0.98	D
MutationAssessor	Pathogenic	4.4	H;H;H;.;H;.;.;.;H;.;.;.;H;.;.;.;.;H;.;.;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.1	D;.;D;D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;.;D;D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.;.
Vest4		0.86
MutPred		0.88		Loss of catalytic residue at P466 (P = 0.0135);Loss of catalytic residue at P466 (P = 0.0135);Loss of catalytic residue at P466 (P = 0.0135);.;Loss of catalytic residue at P466 (P = 0.0135);.;.;.;Loss of catalytic residue at P466 (P = 0.0135);.;.;.;Loss of catalytic residue at P466 (P = 0.0135);.;.;.;.;Loss of catalytic residue at P466 (P = 0.0135);.;.;Loss of catalytic residue at P466 (P = 0.0135);.;.;.;.;Loss of catalytic residue at P466 (P = 0.0135);Loss of catalytic residue at P466 (P = 0.0135);
MVP		0.92
MPC		1.7
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.93
gMVP		0.95

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: rs1057518926; hg19: chr3-71026826;