1-218346056-G-GCACA

Position:

• chr1-218346056-G-GCACA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_003238.6(TGFB2):​c.-624_-621dupACAC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 145,660 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.011 (16 hom., cov: 28)
• Consequence: TGFB2 NM_003238.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.715

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1542/145660) while in subpopulation AFR AF= 0.0278 (1105/39690). AF 95% confidence interval is 0.0265. There are 16 homozygotes in gnomad4. There are 772 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1542 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.-624_-621dupACAC		5_prime_UTR_variant	1/7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.-624_-621dupACAC		5_prime_UTR_variant	1/8		NP_001129071.1
TGFB2	NR_138148.2	n.743_746dupACAC		non_coding_transcript_exon_variant	1/7
TGFB2	NR_138149.2	n.743_746dupACAC		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930	c.-624_-621dupACAC		5_prime_UTR_variant	1/7	1	NM_003238.6	ENSP00000355897.4
TGFB2-AS1	ENST00000414452.2	n.-45_-42dupTGTG		upstream_gene_variant		3
TGFB2-AS1	ENST00000689961.2	n.-24_-21dupTGTG		upstream_gene_variant
TGFB2-AS1	ENST00000691401.1	n.-52_-49dupTGTG		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1533 AN: 145582 Hom.: 15 Cov.: 28

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00715

Gnomad ASJ AF: 0.000589

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.00501

Gnomad FIN AF: 0.00705

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.00180

Gnomad OTH AF: 0.0111

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0106 AC: 1542 AN: 145660 Hom.: 16 Cov.: 28 AF XY: 0.0109 AC XY: 772 AN XY: 70938

Gnomad4 AFR AF: 0.0278

Gnomad4 AMR AF: 0.00714

Gnomad4 ASJ AF: 0.000589

Gnomad4 EAS AF: 0.0205

Gnomad4 SAS AF: 0.00501

Gnomad4 FIN AF: 0.00705

Gnomad4 NFE AF: 0.00180

Gnomad4 OTH AF: 0.0115

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs151329324; hg19: chr1-218519398;