6-41585475-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001012426.2(FOXP4):c.468G>T(p.Gln156His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FOXP4 NM_001012426.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP4	NM_001012426.2	c.468G>T	p.Gln156His	missense_variant	5/17	ENST00000307972.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP4	ENST00000307972.10	c.468G>T	p.Gln156His	missense_variant	5/17	1	NM_001012426.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461646 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.468G>T (p.Q156H) alteration is located in exon 5 (coding exon 4) of the FOXP4 gene. This alteration results from a G to T substitution at nucleotide position 468, causing the glutamine (Q) at amino acid position 156 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;.;.;.;D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D;D;.
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.1	M;M;.;.;M
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;T;D
Polyphen		0.99	D;.;.;.;D
Vest4		0.70
MutPred		0.22		Gain of catalytic residue at L158 (P = 0.078);Gain of catalytic residue at L158 (P = 0.078);Gain of catalytic residue at L158 (P = 0.078);.;Gain of catalytic residue at L158 (P = 0.078);
MVP		0.77
MPC		0.39
ClinPred		0.97	D
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-41553213;