chr3-70977658-T-C

Variant names:

• chr3-70977658-T-C
• rs144080925
• NM_001349338.3:c.1413A>G
• FOXP1 p.Ala471Ala

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001349338.3(FOXP1):​c.1413A>G​(p.Ala471Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,613,400 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (19 hom.)
• Consequence: FOXP1 NM_001349338.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.20
• 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: Illumina, ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000285708 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 3-70977658-T-C is Benign according to our data. Variant chr3-70977658-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00117 (178/152386) while in subpopulation SAS AF = 0.00973 (47/4830). AF 95% confidence interval is 0.00752. There are 1 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 178 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.1413A>G	p.Ala471Ala	synonymous	Exon 16 of 21	NP_001336267.1	Q548T7
	FOXP1	NM_001244810.2		c.1413A>G	p.Ala471Ala	synonymous	Exon 16 of 21	NP_001231739.1	Q9H334-8
	FOXP1	NM_001244814.3		c.1413A>G	p.Ala471Ala	synonymous	Exon 12 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.1413A>G	p.Ala471Ala	synonymous	Exon 16 of 21	ENSP00000497369.1	Q9H334-1
	FOXP1	ENST00000318789.11	TSL:1	c.1413A>G	p.Ala471Ala	synonymous	Exon 16 of 21	ENSP00000318902.5	Q9H334-1
	ENSG00000285708	ENST00000647725.1		c.1413A>G	p.Ala471Ala	synonymous	Exon 21 of 26	ENSP00000497585.1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152268 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00972

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00230 AC: 577 AN: 251370 AF XY: 0.00288

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.000959

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00187 AC: 2727 AN: 1461014 Hom.: 19 Cov.: 31 AF XY: 0.00225 AC XY: 1637 AN XY: 726896

African (AFR) AF: 0.000239 AC: 8 AN: 33470

American (AMR) AF: 0.00157 AC: 70 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0129 AC: 1115 AN: 86230

European-Finnish (FIN) AF: 0.00129 AC: 69 AN: 53374

Middle Eastern (MID) AF: 0.00490 AC: 28 AN: 5720

European-Non Finnish (NFE) AF: 0.00121 AC: 1344 AN: 1111308

Other (OTH) AF: 0.00144 AC: 87 AN: 60366

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152386 Hom.: 1 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74528

African (AFR) AF: 0.000240 AC: 10 AN: 41592

American (AMR) AF: 0.000784 AC: 12 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00973 AC: 47 AN: 4830

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000786

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	FOXP1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Benign	0.65
PhyloP100		2.2
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs144080925;

hg19: chr3-71026809;