NM_001349338.3:c.180+49T>C

Variant names:

• chr3-71198153-A-G
• rs2037474
• NM_001349338.3:c.180+49T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001349338.3(FOXP1):​c.180+49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,613,662 control chromosomes in the GnomAD database, including 24,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3363 hom., cov: 32)
  • Exomes 𝑓: 0.15 (20716 hom.)
• Consequence: FOXP1 NM_001349338.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.947
• Publications: 8 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

ENSG00000285708 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-71198153-A-G is Benign according to our data. Variant chr3-71198153-A-G is described in ClinVar as Benign. ClinVar VariationId is 1273741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP1	NM_001349338.3	c.180+49T>C		intron_variant	Intron 6 of 20	ENST00000649528.3	NP_001336267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP1	ENST00000649528.3	c.180+49T>C		intron_variant	Intron 6 of 20		NM_001349338.3	ENSP00000497369.1
ENSG00000285708	ENST00000647725.1	c.180+49T>C		intron_variant	Intron 11 of 25			ENSP00000497585.1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29390 AN: 152142 Hom.: 3370 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.177

GnomAD2 exomes AF: 0.210 AC: 52567 AN: 250828 AF XY: 0.200

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.404

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.152 AC: 221904 AN: 1461402 Hom.: 20716 Cov.: 35 AF XY: 0.153 AC XY: 111427 AN XY: 727024

African (AFR) AF: 0.270 AC: 9039 AN: 33472

American (AMR) AF: 0.388 AC: 17357 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2749 AN: 26134

East Asian (EAS) AF: 0.350 AC: 13894 AN: 39696

South Asian (SAS) AF: 0.246 AC: 21222 AN: 86248

European-Finnish (FIN) AF: 0.144 AC: 7658 AN: 53280

Middle Eastern (MID) AF: 0.131 AC: 757 AN: 5766

European-Non Finnish (NFE) AF: 0.125 AC: 139366 AN: 1111706

Other (OTH) AF: 0.163 AC: 9862 AN: 60390

GnomAD4 genome AF: 0.193 AC: 29400 AN: 152260 Hom.: 3363 Cov.: 32 AF XY: 0.196 AC XY: 14587 AN XY: 74450

African (AFR) AF: 0.266 AC: 11066 AN: 41530

American (AMR) AF: 0.255 AC: 3895 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 354 AN: 3470

East Asian (EAS) AF: 0.406 AC: 2103 AN: 5178

South Asian (SAS) AF: 0.249 AC: 1201 AN: 4822

European-Finnish (FIN) AF: 0.152 AC: 1612 AN: 10624

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8652 AN: 68016

Other (OTH) AF: 0.175 AC: 371 AN: 2114

Alfa AF: 0.153 Hom.: 4140

Bravo AF: 0.208

Asia WGS AF: 0.324 AC: 1126 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.10
DANN	Benign	0.56
PhyloP100		-0.95
PromoterAI		-0.017	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2037474; hg19: chr3-71247304; COSMIC: COSV59521684;