rs1060501982

Variant names:

• chr1-218347023-A-T
• rs1060501982
• NM_003238.6:c.322A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS2

The NM_001135599.4(TGFB2):​c.322A>T​(p.Met108Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,447,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TGFB2 NM_001135599.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135599.4. 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.322A>T	p.Met108Leu	missense	Exon 1 of 7	NP_003229.1
	TGFB2	NM_001135599.4		c.322A>T	p.Met108Leu	missense	Exon 1 of 8	NP_001129071.1
	TGFB2	NR_138148.2		n.1688A>T		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.322A>T	p.Met108Leu	missense	Exon 1 of 7	ENSP00000355897.4
	TGFB2	ENST00000366929.4	TSL:1	c.322A>T	p.Met108Leu	missense	Exon 1 of 8	ENSP00000355896.4
	TGFB2-AS1	ENST00000774588.1		n.238+606T>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1447626 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718952

African (AFR) AF: 0.00 AC: 0 AN: 33180

American (AMR) AF: 0.00 AC: 0 AN: 42332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.00 AC: 0 AN: 39154

South Asian (SAS) AF: 0.00 AC: 0 AN: 84694

European-Finnish (FIN) AF: 0.0000767 AC: 4 AN: 52130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104736

Other (OTH) AF: 0.00 AC: 0 AN: 59872

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Loeys-Dietz syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.033	D
Polyphen		0.84	P
Vest4		0.44
MutPred		0.71		Loss of ubiquitination at K105 (P = 0.0613)
MVP		0.89
MPC		0.74
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.61
gMVP		0.66
Mutation Taster		=76/24	polymorphism

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: rs1060501982; hg19: chr1-218520365;