3-71198369-A-T

Variant names:

• chr3-71198369-A-T
• rs762898505
• NM_001349338.3:c.13T>A

Variant summary

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

The NM_001349338.3(FOXP1):​c.13T>A​(p.Ser5Thr) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S5P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXP1 NM_001349338.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.37
• Publications: 0 publications found

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

ENSG00000285708 (HGNC:):

ACMG classification

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	c.13T>A	p.Ser5Thr	missense_variant	Exon 6 of 21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3	c.13T>A	p.Ser5Thr	missense_variant	Exon 6 of 21		NM_001349338.3	ENSP00000497369.1
ENSG00000285708	ENST00000647725.1	c.13T>A	p.Ser5Thr	missense_variant	Exon 11 of 26			ENSP00000497585.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;T;.;T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.0	.;D;.;.;.;.;D;.;D;.;D;D;.;D;D;D;D;D;D;D;.;.;.;D;D;.;D;.;.
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.3	M;M;M;M;M;.;.;M;.;M;M;.;M;M;M;.;.;.;.;.;M;M;M;M;.;.;.;.;.
PhyloP100		8.4
PROVEAN	Benign	-1.2	N;.;N;N;.;.;.;.;.;N;N;.;.;.;.;N;.;.;.;.;.;D;.;.;.;.;.;.;.
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;.;D;D;.;.;.;.;.;D;D;.;.;.;.;D;.;.;.;.;.;D;.;.;.;.;.;.;.
Sift4G	Benign	0.18	T;T;T;T;.;.;.;.;.;T;D;.;.;.;.;T;.;.;.;.;D;D;.;.;.;.;.;.;.
Vest4		0.64
ClinPred		0.98	D
GERP RS		5.9
PromoterAI		-0.11	Neutral
Varity_R		0.54
gMVP		0.49
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs762898505; hg19: chr3-71247520;