1-218441563-A-T

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.*201A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 454,240 control chromosomes in the GnomAD database, including 27,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9057 hom., cov: 32)
  • Exomes 𝑓: 0.32 (18161 hom.)
• Consequence: TGFB2 NM_003238.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.320

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-218441563-A-T is Benign according to our data. Variant chr1-218441563-A-T is described in ClinVar as [Benign]. Clinvar id is 295498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB2	NM_003238.6	c.*201A>T		3_prime_UTR_variant	7/7	ENST00000366930.9
TGFB2	NM_001135599.4	c.*201A>T		3_prime_UTR_variant	8/8
TGFB2	NR_138148.2	n.2697A>T		non_coding_transcript_exon_variant	7/7
TGFB2	NR_138149.2	n.2781A>T		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB2	ENST00000366930.9	c.*201A>T		3_prime_UTR_variant	7/7	1	NM_003238.6	P1
TGFB2	ENST00000366929.4	c.*201A>T		3_prime_UTR_variant	8/8	1
TGFB2	ENST00000479322.1	n.930A>T		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50222 AN: 151894 Hom.: 9044 Cov.: 32

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.704

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.323 AC: 97544 AN: 302228 Hom.: 18161 Cov.: 5 AF XY: 0.322 AC XY: 49795 AN XY: 154690

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.496

Gnomad4 ASJ exome AF: 0.314

Gnomad4 EAS exome AF: 0.711

Gnomad4 SAS exome AF: 0.330

Gnomad4 FIN exome AF: 0.304

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.322

GnomAD4 genome AF: 0.331 AC: 50271 AN: 152012 Hom.: 9057 Cov.: 32 AF XY: 0.337 AC XY: 25046 AN XY: 74312

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.446

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.704

Gnomad4 SAS AF: 0.349

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.337

Alfa AF: 0.299 Hom.: 943

Bravo AF: 0.346

Asia WGS AF: 0.468 AC: 1625 AN: 3478

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

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	4.5
Dann	Benign	0.87

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: rs900; hg19: chr1-218614905;