rs4803455

Variant names:

• chr19-41345604-C-A
• rs4803455
• NM_000660.7:c.517-740G>T

Variant summary

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

The NM_000660.7(TGFB1):​c.517-740G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 151,770 control chromosomes in the GnomAD database, including 19,658 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 0.50 (19658 hom., cov: 33)
• Consequence: TGFB1 NM_000660.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.937
• Publications: 113 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.517-740G>T		intron_variant	Intron 2 of 6	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.517-740G>T		intron_variant	Intron 2 of 6		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.517-740G>T		intron_variant	Intron 2 of 6	1	NM_000660.7	ENSP00000221930.4
TGFB1	ENST00000597453.1	n.48-740G>T		intron_variant	Intron 1 of 2	1
TGFB1	ENST00000600196.2	c.517-740G>T		intron_variant	Intron 2 of 5	5		ENSP00000504008.1
TGFB1	ENST00000677934.1	c.517-740G>T		intron_variant	Intron 2 of 4			ENSP00000504769.1

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76488 AN: 151648 Hom.: 19658 Cov.: 33

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.504 AC: 76518 AN: 151770 Hom.: 19658 Cov.: 33 AF XY: 0.505 AC XY: 37419 AN XY: 74152

African (AFR) AF: 0.569 AC: 23567 AN: 41420

American (AMR) AF: 0.405 AC: 6171 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1330 AN: 3462

East Asian (EAS) AF: 0.374 AC: 1908 AN: 5106

South Asian (SAS) AF: 0.470 AC: 2260 AN: 4812

European-Finnish (FIN) AF: 0.601 AC: 6333 AN: 10542

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.490 AC: 33270 AN: 67892

Other (OTH) AF: 0.475 AC: 998 AN: 2102

Alfa AF: 0.487 Hom.: 77563

Bravo AF: 0.491

Asia WGS AF: 0.423 AC: 1467 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.2
DANN	Benign	0.63
PhyloP100		0.94
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4803455; hg19: chr19-41851509;