1-218442986-T-A

Position:

• chr1-218442986-T-A

Variant summary

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

The ENST00000366930.9(TGFB2):​c.*1624T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,158 control chromosomes in the GnomAD database, including 1,075 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1075 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TGFB2 ENST00000366930.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.130

Genes affected

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-OT1 (HGNC:50629): (TGFB2 overlapping transcript 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-218442986-T-A is Benign according to our data. Variant chr1-218442986-T-A is described in ClinVar as [Benign]. Clinvar id is 295521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.*1624T>A		3_prime_UTR_variant	7/7	ENST00000366930.9	NP_003229.1
TGFB2-OT1	NR_125715.1	n.361T>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.*1624T>A		3_prime_UTR_variant	7/7	1	NM_003238.6	ENSP00000355897	P1
TGFB2	ENST00000366929.4	c.*1624T>A		3_prime_UTR_variant	8/8	1		ENSP00000355896
TGFB2-OT1	ENST00000625474.1	n.361T>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15427 AN: 152040 Hom.: 1072 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0655

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.0565

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0550

Gnomad OTH AF: 0.103

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.102 AC: 15460 AN: 152158 Hom.: 1075 Cov.: 32 AF XY: 0.103 AC XY: 7659 AN XY: 74406

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.0655

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.0555

Gnomad4 FIN AF: 0.0585

Gnomad4 NFE AF: 0.0550

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0799 Hom.: 80

Bravo AF: 0.110

Asia WGS AF: 0.107 AC: 371 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.8
DANN	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs3737977; hg19: chr1-218616328;