rs1553303352

Variant names:

• chr1-218437368-C-A
• rs1553303352
• NM_003238.6:c.958C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-218437368-C-A
• chr1-218437368-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_003238.6(TGFB2):​c.958C>A​(p.Arg320Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R320C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TGFB2 NM_003238.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 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):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-218437368-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.958C>A	p.Arg320Ser	missense_variant	Exon 6 of 7	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.1042C>A	p.Arg348Ser	missense_variant	Exon 7 of 8		NP_001129071.1
TGFB2	NR_138148.2	n.2209C>A		non_coding_transcript_exon_variant	Exon 6 of 7
TGFB2	NR_138149.2	n.2293C>A		non_coding_transcript_exon_variant	Exon 7 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.958C>A	p.Arg320Ser	missense_variant	Exon 6 of 7	1	NM_003238.6	ENSP00000355897.4
TGFB2	ENST00000366929.4	c.1042C>A	p.Arg348Ser	missense_variant	Exon 7 of 8	1		ENSP00000355896.4
TGFB2	ENST00000479322.1	n.442C>A		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454378 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 723334

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33170

American (AMR) AF: 0.00 AC: 0 AN: 43762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 84444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108636

Other (OTH) AF: 0.00 AC: 0 AN: 60106

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	2.9	M;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.79		Loss of sheet (P = 0.1398);.;
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.87
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553303352; hg19: chr1-218610710;