NM_003238.6:c.-624_-621dupACAC

Variant names:

• chr1-218346056-G-GCACA
• rs151329324
• NM_003238.6:c.-624_-621dupACAC

Variant summary

Our verdict is Likely benign. The variant received -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
• 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: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1542 AD gene.

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.-624_-621dupACAC		5_prime_UTR	Exon 1 of 7	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.-624_-621dupACAC		5_prime_UTR	Exon 1 of 8	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.743_746dupACAC		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.-624_-621dupACAC		5_prime_UTR	Exon 1 of 7	ENSP00000355897.4	P61812-1
	TGFB2-AS1	ENST00000774588.1		n.239-672_239-669dupTGTG		intron	N/A
	TGFB2-AS1	ENST00000774589.1		n.32-672_32-669dupTGTG		intron	N/A

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

African (AFR) AF: 0.0278 AC: 1105 AN: 39690

American (AMR) AF: 0.00714 AC: 105 AN: 14702

Ashkenazi Jewish (ASJ) AF: 0.000589 AC: 2 AN: 3398

East Asian (EAS) AF: 0.0205 AC: 97 AN: 4724

South Asian (SAS) AF: 0.00501 AC: 22 AN: 4390

European-Finnish (FIN) AF: 0.00705 AC: 68 AN: 9644

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.00180 AC: 119 AN: 65958

Other (OTH) AF: 0.0115 AC: 23 AN: 1996

Alfa AF: 0.00256 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;