6-41584841-C-T

Position:

• chr6-41584841-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001012426.2(FOXP4):​c.373C>T​(p.Pro125Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXP4 NM_001012426.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80

Genes affected

FOXP4 (HGNC:20842): (forkhead box P4) 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. Many members of the forkhead box gene family, including members of subfamily P, have roles in mammalian oncogenesis. This gene may play a role in the development of tumors of the kidney and larynx. Alternative splicing of this gene produces multiple transcript variants, some encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17109928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP4	NM_001012426.2	c.373C>T	p.Pro125Ser	missense_variant	4/17	ENST00000307972.10	NP_001012426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP4	ENST00000307972.10	c.373C>T	p.Pro125Ser	missense_variant	4/17	1	NM_001012426.2	ENSP00000309823.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T;T;T;D;.
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.6	L;L;.;L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.35	N;N;N;N;N
REVEL	Benign	0.072
Sift	Benign	0.56	T;T;T;T;T
Sift4G	Benign	0.62	T;T;T;T;T
Polyphen		0.0	B;.;.;.;B
Vest4		0.32
MutPred		0.099		Loss of catalytic residue at P124 (P = 0.0121);Loss of catalytic residue at P124 (P = 0.0121);Loss of catalytic residue at P124 (P = 0.0121);Loss of catalytic residue at P124 (P = 0.0121);Loss of catalytic residue at P124 (P = 0.0121);
MVP		0.61
MPC		0.066
ClinPred		0.38	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.50

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: rs1766009292; hg19: chr6-41552579;