1-218441563-A-T

Variant names:

• chr1-218441563-A-T
• rs900
• NM_003238.6:c.*201A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003238.6(TGFB2):​c.*201A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 454,240 control chromosomes in the GnomAD database, including 27,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9057 hom., cov: 32)
  • Exomes 𝑓: 0.32 (18161 hom.)
• Consequence: TGFB2 NM_003238.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.320
• Publications: 31 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 Gene-Disease associations (from GenCC):

• Loeys-Dietz syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-218441563-A-T is Benign according to our data. Variant chr1-218441563-A-T is described in ClinVar as Benign. ClinVar VariationId is 295498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 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.*201A>T		3_prime_UTR	Exon 7 of 7	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.*201A>T		3_prime_UTR	Exon 8 of 8	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.2697A>T		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.*201A>T		3_prime_UTR	Exon 7 of 7	ENSP00000355897.4	P61812-1
	TGFB2	ENST00000366929.4	TSL:1	c.*201A>T		3_prime_UTR	Exon 8 of 8	ENSP00000355896.4	P61812-2
	TGFB2	ENST00000479322.1	TSL:3	n.930A>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50222 AN: 151894 Hom.: 9044 Cov.: 32

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.704

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.323 AC: 97544 AN: 302228 Hom.: 18161 Cov.: 5 AF XY: 0.322 AC XY: 49795 AN XY: 154690

African (AFR) AF: 0.364 AC: 2873 AN: 7886

American (AMR) AF: 0.496 AC: 4400 AN: 8878

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 3082 AN: 9828

East Asian (EAS) AF: 0.711 AC: 15997 AN: 22486

South Asian (SAS) AF: 0.330 AC: 3767 AN: 11420

European-Finnish (FIN) AF: 0.304 AC: 6230 AN: 20472

Middle Eastern (MID) AF: 0.319 AC: 451 AN: 1414

European-Non Finnish (NFE) AF: 0.272 AC: 54851 AN: 201552

Other (OTH) AF: 0.322 AC: 5893 AN: 18292

GnomAD4 genome AF: 0.331 AC: 50271 AN: 152012 Hom.: 9057 Cov.: 32 AF XY: 0.337 AC XY: 25046 AN XY: 74312

African (AFR) AF: 0.350 AC: 14486 AN: 41444

American (AMR) AF: 0.446 AC: 6803 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1062 AN: 3464

East Asian (EAS) AF: 0.704 AC: 3639 AN: 5172

South Asian (SAS) AF: 0.349 AC: 1684 AN: 4822

European-Finnish (FIN) AF: 0.305 AC: 3225 AN: 10562

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18253 AN: 67970

Other (OTH) AF: 0.337 AC: 711 AN: 2110

Alfa AF: 0.299 Hom.: 943

Bravo AF: 0.346

Asia WGS AF: 0.468 AC: 1625 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Loeys-Dietz syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.5
DANN	Benign	0.87
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs900; hg19: chr1-218614905;