1-218346056-GCACACACACACACACA-GCACACACACACACACACACACA

Variant names:

• chr1-218346056-G-GCACACA
• rs151329324
• NM_003238.6:c.-626_-621dupACACAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_003238.6(TGFB2):​c.-626_-621dupACACAC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 145,622 control chromosomes in the GnomAD database, including 57 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.016 (57 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
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003238.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	NM_003238.6	MANE Select	c.-626_-621dupACACAC		5_prime_UTR	Exon 1 of 7	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.-626_-621dupACACAC		5_prime_UTR	Exon 1 of 8	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.741_746dupACACAC		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.-626_-621dupACACAC		5_prime_UTR	Exon 1 of 7	ENSP00000355897.4	P61812-1
	TGFB2-AS1	ENST00000774588.1		n.239-674_239-669dupTGTGTG		intron	N/A
	TGFB2-AS1	ENST00000774589.1		n.32-674_32-669dupTGTGTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2340 AN: 145544 Hom.: 57 Cov.: 28

Gnomad AFR AF: 0.0543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.000683

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.000364

Gnomad OTH AF: 0.00960

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

GnomAD4 genome AF: 0.0161 AC: 2340 AN: 145622 Hom.: 57 Cov.: 28 AF XY: 0.0155 AC XY: 1098 AN XY: 70928

African (AFR) AF: 0.0542 AC: 2148 AN: 39654

American (AMR) AF: 0.00646 AC: 95 AN: 14700

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 38 AN: 3396

East Asian (EAS) AF: 0.00233 AC: 11 AN: 4724

South Asian (SAS) AF: 0.000683 AC: 3 AN: 4390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9648

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.000364 AC: 24 AN: 65958

Other (OTH) AF: 0.00953 AC: 19 AN: 1994

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Loeys-Dietz syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.71

Splicing

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

Other links and lift over

dbSNP: rs151329324; hg19: chr1-218519398;