rs587777855

Positions:

• chr3-70972607-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001349338.3(FOXP1):​c.1600T>C​(p.Trp534Arg) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 3-70972607-A-G is Pathogenic according to our data. Variant chr3-70972607-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 156541.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.1600T>C	p.Trp534Arg	missense_variant	18/21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3	c.1600T>C	p.Trp534Arg	missense_variant	18/21		NM_001349338.3	ENSP00000497369	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;.;D;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;.;.;.;D;.;D;D;D;.;.;D;D;.;.;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	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	0.99	D
MutationAssessor	Pathogenic	4.2	H;H;.;H;.;.;.;.;.;.;H;.;.;.;.;H;.;.;H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-12	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;.;D;.;.;.;.;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.98
MutPred		0.90		Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);.;Gain of disorder (P = 0.0092);.;.;.;.;.;.;Gain of disorder (P = 0.0092);.;.;.;.;Gain of disorder (P = 0.0092);.;.;Gain of disorder (P = 0.0092);.;.;.;Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);
MVP		0.98
MPC		4.9
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587777855; hg19: chr3-71021758;