6-41585463-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001012426.2(FOXP4):c.456G>A(p.Gln152=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: FOXP4 NM_001012426.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.20

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 Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 6-41585463-G-A is Benign according to our data. Variant chr6-41585463-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 715573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.2 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP4	NM_001012426.2	c.456G>A	p.Gln152=	synonymous_variant	5/17	ENST00000307972.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP4	ENST00000307972.10	c.456G>A	p.Gln152=	synonymous_variant	5/17	1	NM_001012426.2	P4

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000841 AC: 211 AN: 250980 Hom.: 0 AF XY: 0.000833 AC XY: 113 AN XY: 135734

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00123 AC: 1791 AN: 1461650 Hom.: 1 Cov.: 31 AF XY: 0.00119 AC XY: 863 AN XY: 727148

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000793 AC XY: 59 AN XY: 74438

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000884 Hom.: 0

Bravo AF: 0.000956

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	FOXP4: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	4.1
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs148022939; hg19: chr6-41553201; COSMIC: COSV57221291; COSMIC: COSV57221291;