3-70955832-GCACA-G

Position:

• chr3-70955832-GCACA-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001349338.3(FOXP1):​c.*3411_*3414del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 220,820 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 26)
  • Exomes 𝑓: 0.0047 (0 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.435

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 3-70955832-GCACA-G is Benign according to our data. Variant chr3-70955832-GCACA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 346568.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00319 (469/147234) while in subpopulation SAS AF= 0.011 (51/4640). AF 95% confidence interval is 0.00859. There are 2 homozygotes in gnomad4. There are 257 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 469 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*3411_*3414del		3_prime_UTR_variant	21/21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3	c.*3411_*3414del		3_prime_UTR_variant	21/21		NM_001349338.3	ENSP00000497369	P4
FOXP1	ENST00000318789.11	c.*3411_*3414del		3_prime_UTR_variant	21/21	1		ENSP00000318902	P4

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 470 AN: 147138 Hom.: 2 Cov.: 26

Gnomad AFR AF: 0.000943

Gnomad AMI AF: 0.00224

Gnomad AMR AF: 0.00547

Gnomad ASJ AF: 0.00470

Gnomad EAS AF: 0.000597

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.000733

Gnomad MID AF: 0.0256

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.0114

GnomAD4 exome AF: 0.00470 AC: 346 AN: 73586 Hom.: 0 AF XY: 0.00494 AC XY: 167 AN XY: 33786

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00752

Gnomad4 ASJ exome AF: 0.00632

Gnomad4 EAS exome AF: 0.000454

Gnomad4 SAS exome AF: 0.00710

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00525

Gnomad4 OTH exome AF: 0.00659

GnomAD4 genome AF: 0.00319 AC: 469 AN: 147234 Hom.: 2 Cov.: 26 AF XY: 0.00359 AC XY: 257 AN XY: 71602

Gnomad4 AFR AF: 0.000940

Gnomad4 AMR AF: 0.00546

Gnomad4 ASJ AF: 0.00470

Gnomad4 EAS AF: 0.000598

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.000733

Gnomad4 NFE AF: 0.00365

Gnomad4 OTH AF: 0.0112

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FOXP1: BS1 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual Disability with Language Impairment and Autistic Features Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs143202281; hg19: chr3-71004983;