rs763918203

chr1-218346738-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_003238.6(TGFB2):c.37C>A(p.His13Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H13R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: TGFB2 NM_003238.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.75

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10244018).
• BP6: Variant 1-218346738-C-A is Benign according to our data. Variant chr1-218346738-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 295485.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS2: High AC in GnomAdExome at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB2	NM_003238.6	c.37C>A	p.His13Asn	missense_variant	1/7	ENST00000366930.9
TGFB2	NM_001135599.4	c.37C>A	p.His13Asn	missense_variant	1/8
TGFB2	NR_138148.2	n.1403C>A		non_coding_transcript_exon_variant	1/7
TGFB2	NR_138149.2	n.1403C>A		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB2	ENST00000366930.9	c.37C>A	p.His13Asn	missense_variant	1/7	1	NM_003238.6	P1
TGFB2	ENST00000366929.4	c.37C>A	p.His13Asn	missense_variant	1/8	1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 250968 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461596 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

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: 0.0000153

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Loeys-Dietz syndrome 4 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 31, 2022	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 13 of the TGFB2 protein (p.His13Asn). This variant is present in population databases (rs763918203, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TGFB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 295485). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TGFB2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

TGFB2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2023

The TGFB2 c.37C>A variant is predicted to result in the amino acid substitution p.His13Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.015% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-218520080-C-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Benign	0.85
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.11	N;N
MutationTaster	Benign	0.57	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.0	B;B
Vest4		0.31
MVP		0.69
MPC		0.81
ClinPred		0.079	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.21

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: rs763918203; hg19: chr1-218520080;