chr3-70956415-C-CTT

Variant names:

• chr3-70956415-C-CTT
• rs112098084
• NM_001349338.3:c.*2830_*2831dupAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001349338.3(FOXP1):​c.*2830_*2831dupAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 186,380 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0037 (0 hom.)
• Consequence: FOXP1 NM_001349338.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.961
• Publications: 0 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: Illumina, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000524 (66/125944) while in subpopulation NFE AF = 0.000657 (39/59398). AF 95% confidence interval is 0.000494. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.*2830_*2831dupAA		3_prime_UTR_variant	Exon 21 of 21	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3	c.*2830_*2831dupAA		3_prime_UTR_variant	Exon 21 of 21		NM_001349338.3	ENSP00000497369.1
FOXP1	ENST00000318789.11	c.*2830_*2831dupAA		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000318902.5

Frequencies

GnomAD3 genomes AF: 0.000524 AC: 66 AN: 125938 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000272

Gnomad AMI AF: 0.00125

Gnomad AMR AF: 0.000632

Gnomad ASJ AF: 0.000639

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000515

Gnomad FIN AF: 0.000723

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000656

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00367 AC: 222 AN: 60436 Hom.: 0 Cov.: 0 AF XY: 0.00340 AC XY: 95 AN XY: 27938

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00143 AC: 4 AN: 2792

American (AMR) AF: 0.00611 AC: 11 AN: 1800

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 16 AN: 3728

East Asian (EAS) AF: 0.000971 AC: 9 AN: 9270

South Asian (SAS) AF: 0.00198 AC: 1 AN: 506

European-Finnish (FIN) AF: 0.00265 AC: 1 AN: 378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 380

European-Non Finnish (NFE) AF: 0.00435 AC: 159 AN: 36524

Other (OTH) AF: 0.00415 AC: 21 AN: 5058

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000524 AC: 66 AN: 125944 Hom.: 0 Cov.: 26 AF XY: 0.000512 AC XY: 31 AN XY: 60540

African (AFR) AF: 0.000271 AC: 9 AN: 33150

American (AMR) AF: 0.000631 AC: 8 AN: 12674

Ashkenazi Jewish (ASJ) AF: 0.000639 AC: 2 AN: 3132

East Asian (EAS) AF: 0.00 AC: 0 AN: 4088

South Asian (SAS) AF: 0.000519 AC: 2 AN: 3852

European-Finnish (FIN) AF: 0.000723 AC: 5 AN: 6916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.000657 AC: 39 AN: 59398

Other (OTH) AF: 0.00 AC: 0 AN: 1684

Alfa AF: 0.00 Hom.: 45

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs112098084; hg19: chr3-71005566;