1-218442864-T-C

Position:

• chr1-218442864-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000366930.9(TGFB2):​c.*1502T>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 0.0312 in 152,256 control chromosomes in the GnomAD database, including 82 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 (82 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TGFB2 ENST00000366930.9 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.233

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-218442864-T-C is Benign according to our data. Variant chr1-218442864-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 295518.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0312 (4748/152256) while in subpopulation NFE AF= 0.0454 (3089/67984). AF 95% confidence interval is 0.0441. There are 82 homozygotes in gnomad4. There are 2261 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4748 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.*1502T>C		3_prime_UTR_variant	7/7	ENST00000366930.9	NP_003229.1
TGFB2-OT1	NR_125715.1	n.239T>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.*1502T>C		3_prime_UTR_variant	7/7	1	NM_003238.6	ENSP00000355897	P1
TGFB2	ENST00000366929.4	c.*1502T>C		3_prime_UTR_variant	8/8	1		ENSP00000355896
TGFB2-OT1	ENST00000625474.1	n.239T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4751 AN: 152138 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.00958

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0278

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: 0.0312 AC: 4748 AN: 152256 Hom.: 82 Cov.: 32 AF XY: 0.0304 AC XY: 2261 AN XY: 74462

Gnomad4 AFR AF: 0.00952

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.0563

Gnomad4 NFE AF: 0.0454

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0383 Hom.: 20

Bravo AF: 0.0290

Asia WGS AF: 0.00722 AC: 26 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome 4 Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.2
DANN	Benign	0.85

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: rs17500758; hg19: chr1-218616206;