rs12981053

Variant names:

• chr19-41326551-C-T
• rs12981053
• ENST00000598758.5:n.302+5577G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000598758.5(TGFB1):​n.302+5577G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 152,114 control chromosomes in the GnomAD database, including 1,556 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1556 hom., cov: 32)
• Consequence: TGFB1 ENST00000598758.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 9 publications found

Genes affected

TGFB1 (HGNC:11766): (transforming growth factor beta 1) 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 TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]

TGFB1 Gene-Disease associations (from GenCC):

• Camurati-Engelmann disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• inflammatory bowel disease, immunodeficiency, and encephalopathy

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000598758.5	n.302+5577G>A		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19681 AN: 151996 Hom.: 1560 Cov.: 32

Gnomad AFR AF: 0.0660

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.0956

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.138

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.129 AC: 19669 AN: 152114 Hom.: 1556 Cov.: 32 AF XY: 0.127 AC XY: 9464 AN XY: 74382

African (AFR) AF: 0.0658 AC: 2728 AN: 41446

American (AMR) AF: 0.116 AC: 1773 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 558 AN: 3466

East Asian (EAS) AF: 0.272 AC: 1405 AN: 5170

South Asian (SAS) AF: 0.0957 AC: 462 AN: 4828

European-Finnish (FIN) AF: 0.142 AC: 1506 AN: 10604

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10537 AN: 67990

Other (OTH) AF: 0.137 AC: 290 AN: 2114

Alfa AF: 0.149 Hom.: 736

Bravo AF: 0.129

Asia WGS AF: 0.190 AC: 661 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.7
DANN	Benign	0.80
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12981053; hg19: chr19-41832456;