dbSNP rs749611196: FOXP1:p.Met102Ile (chr3-71053750-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001349338.3(FOXP1):c.306G>C(p.Met102Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

FOXP1
NM_001349338.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.90

Publications

0 publications found

Variant links:

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]

FOXP1 Gene-Disease associations (from GenCC):

intellectual disability-severe speech delay-mild dysmorphism syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

FOXP1 links:

ENSG00000285708 (HGNC:):

ENSG00000285708 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3 link	c.306G>C	p.Met102Ile	missense_variant	Exon 8 of 21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3 link	c.306G>C	p.Met102Ile	missense_variant	Exon 8 of 21		NM_001349338.3	ENSP00000497369.1
ENSG00000285708	ENST00000647725.1 link	c.306G>C	p.Met102Ile	missense_variant	Exon 13 of 26			ENSP00000497585.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;.;D;.;D;.;.;.;.;.;.;.;D;.;.;.;D;.;.;D;.;.;.;.;.;.;.;T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;.;.;.;.;D;.;.;D;D;D;.;.;D;.;.;D;D;D;D;D;D;D;D;D;D;D;.

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.53

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;D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.6

M;M;M;M;M;.;.;.;M;.;.;.;M;.;.;.;M;M;.;M;.;.;.;.;.;.;.;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.6

D;.;D;D;.;.;.;.;.;.;.;.;D;.;.;N;.;.;.;.;.;D;.;.;D;.;D;.;.

REVEL

Benign

0.29

Sift

Benign

0.071

T;.;T;T;.;.;.;.;.;.;.;.;T;.;.;T;.;.;.;.;.;T;.;.;T;.;D;.;.

Sift4G

Benign

0.14

T;T;T;T;.;.;.;T;.;.;.;.;T;.;.;T;.;.;.;.;.;T;.;.;.;.;T;.;.

Polyphen

0.53

P;.;P;.;P;.;.;.;.;.;.;.;P;.;.;.;P;.;.;P;.;.;.;.;.;.;.;.;.

Vest4

0.74

MutPred

0.18

Gain of catalytic residue at P104 (P = 0.0327);Gain of catalytic residue at P104 (P = 0.0327);Gain of catalytic residue at P104 (P = 0.0327);Gain of catalytic residue at P104 (P = 0.0327);Gain of catalytic residue at P104 (P = 0.0327);Gain of catalytic residue at P104 (P = 0.0327);.;.;Gain of catalytic residue at P104 (P = 0.0327);Gain of catalytic residue at P104 (P = 0.0327);.;.;Gain of catalytic residue at P104 (P = 0.0327);.;Gain of catalytic residue at P104 (P = 0.0327);.;Gain of catalytic residue at P104 (P = 0.0327);Gain of catalytic residue at P104 (P = 0.0327);.;Gain of catalytic residue at P104 (P = 0.0327);.;Gain of catalytic residue at P104 (P = 0.0327);.;Gain of catalytic residue at P104 (P = 0.0327);.;.;.;Gain of catalytic residue at P104 (P = 0.0327);Gain of catalytic residue at P104 (P = 0.0327);

MVP

0.79

MPC

0.78

ClinPred

0.94

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.23

Mutation Taster

=17/83

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over