dbSNP rs1553303352: TGFB2:p.Arg320Ser (chr1-218437368-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_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. 12/21 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a chain Transforming growth factor beta-2 (size 111) in uniprot entity TGFB2_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_003238.6

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 [Likely_pathogenic]. Clinvar id 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 link	c.958C>A	p.Arg320Ser	missense_variant	Exon 6 of 7	ENST00000366930.9	NP_003229.1	P61812-1Q59EG9
TGFB2	NM_001135599.4 link	c.1042C>A	p.Arg348Ser	missense_variant	Exon 7 of 8		NP_001129071.1	P61812-2Q59EG9
TGFB2	NR_138148.2 link	n.2209C>A		non_coding_transcript_exon_variant	Exon 6 of 7
TGFB2	NR_138149.2 link	n.2293C>A		non_coding_transcript_exon_variant	Exon 7 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGFB2	ENST00000366930.9 link	c.958C>A	p.Arg320Ser	missense_variant	Exon 6 of 7	1	NM_003238.6	ENSP00000355897.4	P61812-1
TGFB2	ENST00000366929.4 link	c.1042C>A	p.Arg348Ser	missense_variant	Exon 7 of 8	1		ENSP00000355896.4	P61812-2
TGFB2	ENST00000479322.1 link	n.442C>A		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454378

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723334

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Pathogenic

0.90

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

GERP RS

5.8

Varity_R

0.94

gMVP

0.87

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over