NM_003238.6:c.-622_-621delAC

Variant names:

• chr1-218346056-GCA-G
• rs151329324
• NM_003238.6:c.-622_-621delAC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_003238.6(TGFB2):​c.-622_-621delAC 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
• 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1115 AD,Unknown 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.-622_-621delAC		5_prime_UTR	Exon 1 of 7	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.-622_-621delAC		5_prime_UTR	Exon 1 of 8	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.745_746delAC		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.-622_-621delAC		5_prime_UTR	Exon 1 of 7	ENSP00000355897.4	P61812-1
	TGFB2-AS1	ENST00000774588.1		n.239-670_239-669delTG		intron	N/A
	TGFB2-AS1	ENST00000774589.1		n.32-670_32-669delTG		intron	N/A

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

African (AFR) AF: 0.00494 AC: 196 AN: 39654

American (AMR) AF: 0.0107 AC: 157 AN: 14668

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 60 AN: 3392

East Asian (EAS) AF: 0.00487 AC: 23 AN: 4718

South Asian (SAS) AF: 0.0130 AC: 57 AN: 4386

European-Finnish (FIN) AF: 0.00939 AC: 89 AN: 9480

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

European-Non Finnish (NFE) AF: 0.00769 AC: 505 AN: 65710

Other (OTH) AF: 0.0131 AC: 26 AN: 1990

Alfa AF: 0.00175 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely benign

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		-0.34

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; COSMIC: COSV65108342;