1-218345400-A-G

Position:

• chr1-218345400-A-G

Variant summary

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

The NM_003238.6(TGFB2):​c.-1302A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 152,408 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (96 hom., cov: 32)
  • Exomes 𝑓: 0.029 (0 hom.)
• Consequence: TGFB2 NM_003238.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.377

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-218345400-A-G is Benign according to our data. Variant chr1-218345400-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 295455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.-1302A>G		5_prime_UTR_variant	1/7	ENST00000366930.9	NP_003229.1
TGFB2-AS1	NR_046268.1	n.77-12T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.-1302A>G		5_prime_UTR_variant	1/7	1	NM_003238.6	ENSP00000355897	P1
TGFB2-AS1	ENST00000689961.2	n.435-12T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4651 AN: 152186 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.0798

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.0325

GnomAD4 exome AF: 0.0288 AC: 3 AN: 104 Hom.: 0 Cov.: 0 AF XY: 0.0263 AC XY: 2 AN XY: 76

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0417

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0305 AC: 4652 AN: 152304 Hom.: 96 Cov.: 32 AF XY: 0.0292 AC XY: 2173 AN XY: 74470

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.0240

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.0798

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.0219

Gnomad4 NFE AF: 0.0360

Gnomad4 OTH AF: 0.0321

Alfa AF: 0.0325 Hom.: 39

Bravo AF: 0.0321

Asia WGS AF: 0.0260 AC: 91 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.6
DANN	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10482718; hg19: chr1-218518742;