1-218442672-C-T

Variant names:

• chr1-218442672-C-T
• rs1418556
• NM_003238.6:c.*1310C>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.*1310C>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 0.373 in 150,078 control chromosomes in the GnomAD database, including 11,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11279 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TGFB2 NM_003238.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.600

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=-0.91).
• BP6: Variant 1-218442672-C-T is Benign according to our data. Variant chr1-218442672-C-T is described in ClinVar as [Benign]. Clinvar id is 295514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.*1310C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000366930.9	NP_003229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.*1310C>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_003238.6	ENSP00000355897.4
TGFB2	ENST00000366929.4	c.*1310C>T		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000355896.4
TGFB2-OT1	ENST00000625474.1	n.47C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.373 AC: 55944 AN: 149984 Hom.: 11264 Cov.: 30

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.367

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.373 AC: 55991 AN: 150078 Hom.: 11279 Cov.: 30 AF XY: 0.378 AC XY: 27666 AN XY: 73178

Gnomad4 AFR AF: 0.464

Gnomad4 AMR AF: 0.470

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.716

Gnomad4 SAS AF: 0.370

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.370

Alfa AF: 0.149 Hom.: 270

Bravo AF: 0.394

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.69
DANN	Benign	0.32

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: rs1418556; hg19: chr1-218616014;