NM_003238.6:c.322A>T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_003238.6(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_003238.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.322A>T	p.Met108Leu	missense_variant	Exon 1 of 7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.322A>T	p.Met108Leu	missense_variant	Exon 1 of 8		NP_001129071.1
TGFB2	NR_138148.2	n.1688A>T		non_coding_transcript_exon_variant	Exon 1 of 7
TGFB2	NR_138149.2	n.1688A>T		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.322A>T	p.Met108Leu	missense_variant	Exon 1 of 7	1	NM_003238.6	ENSP00000355897.4
TGFB2	ENST00000366929.4	c.322A>T	p.Met108Leu	missense_variant	Exon 1 of 8	1		ENSP00000355896.4
TGFB2	ENST00000488793.1	n.-15A>T		upstream_gene_variant		3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000767

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome 4 Uncertain:1

Oct 08, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TGFB2-related disease. This sequence change replaces methionine with leucine at codon 108 of the TGFB2 protein (p.Met108Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.033	D;T
Polyphen		0.84	P;P
Vest4		0.44
MutPred		0.71		Loss of ubiquitination at K105 (P = 0.0613);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501982; hg19: chr1-218520365;