1-218346056-GCA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_003238.6(TGFB2):c.-622_-621del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00768 in 145,156 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0077 (5 hom., cov: 28)
• Consequence: TGFB2 NM_003238.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.336

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 1-218346056-GCA-G is Benign according to our data. Variant chr1-218346056-GCA-G is described in ClinVar as [Likely_benign]. Clinvar id is 295476.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00768 (1115/145156) while in subpopulation SAS AF= 0.013 (57/4386). AF 95% confidence interval is 0.0103. There are 5 homozygotes in gnomad4. There are 572 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd at 1110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB2	NM_003238.6	c.-622_-621del		5_prime_UTR_variant	1/7	ENST00000366930.9
TGFB2	NM_001135599.4	c.-622_-621del		5_prime_UTR_variant	1/8
TGFB2	NR_138148.2	n.745_746del		non_coding_transcript_exon_variant	1/7
TGFB2	NR_138149.2	n.745_746del		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB2	ENST00000366930.9	c.-622_-621del		5_prime_UTR_variant	1/7	1	NM_003238.6	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: 0.00765 AC: 1110 AN: 145080 Hom.: 5 Cov.: 28

Gnomad AFR AF: 0.00483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0177

Gnomad EAS AF: 0.00485

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00939

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.00768

Gnomad OTH AF: 0.0132

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

GnomAD4 genome AF: 0.00768 AC: 1115 AN: 145156 Hom.: 5 Cov.: 28 AF XY: 0.00809 AC XY: 572 AN XY: 70666

Gnomad4 AFR AF: 0.00494

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.0177

Gnomad4 EAS AF: 0.00487

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.00939

Gnomad4 NFE AF: 0.00769

Gnomad4 OTH AF: 0.0131

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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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;