chr3-70972152-T-C

Position:

• chr3-70972152-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001244810.2(FOXP1):​c.1559A>G​(p.His520Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,532,252 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (69 hom.)
• Consequence: FOXP1 NM_001244810.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.76

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]

ENSG00000285708 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009577841).
• BP6: Variant 3-70972152-T-C is Benign according to our data. Variant chr3-70972152-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 376816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-70972152-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.1652+403A>G		intron_variant		ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3	c.1652+403A>G		intron_variant			NM_001349338.3	ENSP00000497369.1
ENSG00000285708	ENST00000647725.1	c.1652+403A>G		intron_variant				ENSP00000497585.1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 530 AN: 152114 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0395

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00580 AC: 761 AN: 131240 Hom.: 8 AF XY: 0.00553 AC XY: 394 AN XY: 71188

Gnomad AFR exome AF: 0.000466

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.00235

Gnomad EAS exome AF: 0.0366

Gnomad SAS exome AF: 0.000518

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.00595

GnomAD4 exome AF: 0.00232 AC: 3201 AN: 1380020 Hom.: 69 Cov.: 32 AF XY: 0.00227 AC XY: 1546 AN XY: 680786

Gnomad4 AFR exome AF: 0.000351

Gnomad4 AMR exome AF: 0.00979

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0561

Gnomad4 SAS exome AF: 0.000423

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00331

GnomAD4 genome AF: 0.00349 AC: 532 AN: 152232 Hom.: 6 Cov.: 32 AF XY: 0.00429 AC XY: 319 AN XY: 74430

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.0398

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.00332

ExAC AF: 0.00157 AC: 36

Asia WGS AF: 0.0220 AC: 76 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	- -

FOXP1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	17
DANN	Benign	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.
MetaRNN	Benign	0.0096	T;T
Sift4G	Pathogenic	0.0010	D;.
Vest4		0.95
MVP		0.81
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs76145927; hg19: chr3-71021303; COSMIC: COSV59552218;