3-70955832-GCACACACACACA-GCACACACA

Variant names:

• chr3-70955832-GCACA-G
• rs143202281
• NM_001349338.3:c.*3411_*3414delTGTG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001349338.3(FOXP1):​c.*3411_*3414delTGTG 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
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, ClinGen
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 346568.
• 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 the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 469 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP1	NM_001349338.3	MANE Select	c.*3411_*3414delTGTG		3_prime_UTR	Exon 21 of 21	NP_001336267.1	Q548T7
	FOXP1	NM_001244810.2		c.*3411_*3414delTGTG		3_prime_UTR	Exon 21 of 21	NP_001231739.1	Q9H334-8
	FOXP1	NM_001244814.3		c.*3411_*3414delTGTG		3_prime_UTR	Exon 17 of 17	NP_001231743.1	Q9H334-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP1	ENST00000649528.3	MANE Select	c.*3411_*3414delTGTG		3_prime_UTR	Exon 21 of 21	ENSP00000497369.1	Q9H334-1
	FOXP1	ENST00000318789.11	TSL:1	c.*3411_*3414delTGTG		3_prime_UTR	Exon 21 of 21	ENSP00000318902.5	Q9H334-1

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

African (AFR) AF: 0.00132 AC: 5 AN: 3798

American (AMR) AF: 0.00752 AC: 17 AN: 2260

Ashkenazi Jewish (ASJ) AF: 0.00632 AC: 29 AN: 4586

East Asian (EAS) AF: 0.000454 AC: 5 AN: 11012

South Asian (SAS) AF: 0.00710 AC: 5 AN: 704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 310

Middle Eastern (MID) AF: 0.0279 AC: 12 AN: 430

European-Non Finnish (NFE) AF: 0.00525 AC: 233 AN: 44412

Other (OTH) AF: 0.00659 AC: 40 AN: 6074

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

African (AFR) AF: 0.000940 AC: 38 AN: 40408

American (AMR) AF: 0.00546 AC: 80 AN: 14646

Ashkenazi Jewish (ASJ) AF: 0.00470 AC: 16 AN: 3402

East Asian (EAS) AF: 0.000598 AC: 3 AN: 5016

South Asian (SAS) AF: 0.0110 AC: 51 AN: 4640

European-Finnish (FIN) AF: 0.000733 AC: 7 AN: 9544

Middle Eastern (MID) AF: 0.0241 AC: 7 AN: 290

European-Non Finnish (NFE) AF: 0.00365 AC: 242 AN: 66350

Other (OTH) AF: 0.0112 AC: 23 AN: 2046

Alfa AF: 0.00214 Hom.: 6

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Intellectual Disability with Language Impairment and Autistic Features (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism

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: rs143202281; hg19: chr3-71004983;