rs991967

Positions:

• chr1-218442109-A-C
• chr1-218442109-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003238.6(TGFB2):​c.*747A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 151,828 control chromosomes in the GnomAD database, including 11,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (11651 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: TGFB2 NM_003238.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.110

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-218442109-A-C is Benign according to our data. Variant chr1-218442109-A-C is described in ClinVar as [Benign]. Clinvar id is 295502.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB2	NM_003238.6	c.*747A>C		3_prime_UTR_variant	7/7	ENST00000366930.9
TGFB2	NM_001135599.4	c.*747A>C		3_prime_UTR_variant	8/8
TGFB2	NR_138148.2	n.3243A>C		non_coding_transcript_exon_variant	7/7
TGFB2	NR_138149.2	n.3327A>C		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB2	ENST00000366930.9	c.*747A>C		3_prime_UTR_variant	7/7	1	NM_003238.6	P1
TGFB2	ENST00000366929.4	c.*747A>C		3_prime_UTR_variant	8/8	1
TGFB2	ENST00000479322.1	n.1476A>C		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57031 AN: 151708 Hom.: 11628 Cov.: 32

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.369

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

GnomAD4 genome AF: 0.376 AC: 57099 AN: 151826 Hom.: 11651 Cov.: 32 AF XY: 0.381 AC XY: 28285 AN XY: 74208

Gnomad4 AFR AF: 0.467

Gnomad4 AMR AF: 0.474

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.717

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.372

Alfa AF: 0.350 Hom.: 1694

Bravo AF: 0.395

Asia WGS AF: 0.492 AC: 1714 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.89

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: rs991967; hg19: chr1-218615451;