1-218346048-G-GCGCACA

Position:

• chr1-218346048-G-GCGCACA

Variant summary

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

The NM_003238.6(TGFB2):​c.-646_-641dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 140,546 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0069 (5 hom., cov: 31)
• Consequence: TGFB2 NM_003238.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.322

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-AS1 (HGNC:50628): (TGFB2 antisense RNA 1 (head to head))

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00687 (966/140546) while in subpopulation NFE AF= 0.0109 (715/65760). AF 95% confidence interval is 0.0102. There are 5 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 31. 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 966 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.-646_-641dup		5_prime_UTR_variant	1/7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.-646_-641dup		5_prime_UTR_variant	1/8		NP_001129071.1
TGFB2	NR_138148.2	n.721_726dup		non_coding_transcript_exon_variant	1/7
TGFB2	NR_138149.2	n.721_726dup		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.-646_-641dup		5_prime_UTR_variant	1/7	1	NM_003238.6	ENSP00000355897	P1
TGFB2-AS1	ENST00000689961.2			upstream_gene_variant
TGFB2-AS1	ENST00000414452.2			upstream_gene_variant		3
TGFB2-AS1	ENST00000691401.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00688 AC: 966 AN: 140474 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.000896

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00107

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00458

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

GnomAD4 genome AF: 0.00687 AC: 966 AN: 140546 Hom.: 5 Cov.: 31 AF XY: 0.00659 AC XY: 453 AN XY: 68736

Gnomad4 AFR AF: 0.00247

Gnomad4 AMR AF: 0.00302

Gnomad4 ASJ AF: 0.000896

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00107

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00453

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Loeys-Dietz syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 09, 2022

- -

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: rs765496001; hg19: chr1-218519390;