1-218345173-A-C

Variant names:

• chr1-218345173-A-C
• rs7550232
• ENST00000687392.2:n.815T>G

Variant summary

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

The ENST00000687392.2(TGFB2-AS1):​n.815T>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,360 control chromosomes in the GnomAD database, including 6,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (6580 hom., cov: 32)
  • Exomes 𝑓: 0.083 (4 hom.)
• Consequence: TGFB2-AS1 ENST00000687392.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.326
• Publications: 12 publications found

Genes affected

TGFB2-AS1 (HGNC:50628): (TGFB2 antisense RNA 1 (head to head))

TGFB2 (HGNC:11768): (transforming growth factor beta 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

TGFB2 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-218345173-A-C is Benign according to our data. Variant chr1-218345173-A-C is described in ClinVar as Benign. ClinVar VariationId is 1241729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000687392.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2-AS1	NR_046268.1		n.290+2T>G		splice_donor intron	N/A
	TGFB2	NM_003238.6	MANE Select	c.-1529A>C		upstream_gene	N/A	NP_003229.1
	TGFB2	NM_001135599.4		c.-1529A>C		upstream_gene	N/A	NP_001129071.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2-AS1	ENST00000687392.2		n.815T>G		non_coding_transcript_exon	Exon 1 of 1
	TGFB2-AS1	ENST00000689961.3		n.656T>G		non_coding_transcript_exon	Exon 2 of 3
	TGFB2-AS1	ENST00000691401.2		n.632T>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28029 AN: 152086 Hom.: 6555 Cov.: 32

Gnomad AFR AF: 0.553

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0889

Gnomad ASJ AF: 0.0426

Gnomad EAS AF: 0.0827

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.137

GnomAD4 exome AF: 0.0833 AC: 13 AN: 156 Hom.: 4 Cov.: 0 AF XY: 0.0789 AC XY: 9 AN XY: 114

African (AFR) AF: 0.750 AC: 9 AN: 12

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0268 AC: 3 AN: 112

Other (OTH) AF: 0.0500 AC: 1 AN: 20

GnomAD4 genome AF: 0.185 AC: 28106 AN: 152204 Hom.: 6580 Cov.: 32 AF XY: 0.178 AC XY: 13219 AN XY: 74418

African (AFR) AF: 0.553 AC: 22943 AN: 41496

American (AMR) AF: 0.0887 AC: 1357 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0426 AC: 148 AN: 3472

East Asian (EAS) AF: 0.0827 AC: 427 AN: 5164

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4824

European-Finnish (FIN) AF: 0.0222 AC: 236 AN: 10618

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0381 AC: 2593 AN: 68008

Other (OTH) AF: 0.135 AC: 286 AN: 2114

Alfa AF: 0.0753 Hom.: 2507

Bravo AF: 0.208

Asia WGS AF: 0.0610 AC: 212 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

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	13
DANN	Benign	0.58
PhyloP100		-0.33
PromoterAI		0.078	Neutral

Splicing

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

Other links and lift over

dbSNP: rs7550232; hg19: chr1-218518515;