19-41346210-T-C

Variant names:

• chr19-41346210-T-C
• rs1989457
• NM_000660.7:c.517-1346A>G

Variant summary

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

The NM_000660.7(TGFB1):​c.517-1346A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 151,876 control chromosomes in the GnomAD database, including 29,788 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 0.61 (29788 hom., cov: 31)
• Consequence: TGFB1 NM_000660.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.02
• Publications: 7 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.517-1346A>G		intron_variant	Intron 2 of 6	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.517-1346A>G		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.517-1346A>G		intron_variant	Intron 2 of 6	1	NM_000660.7	ENSP00000221930.4
TGFB1	ENST00000597453.1	n.48-1346A>G		intron_variant	Intron 1 of 2	1
TGFB1	ENST00000600196.2	c.517-1346A>G		intron_variant	Intron 2 of 5	5		ENSP00000504008.1
TGFB1	ENST00000677934.1	c.517-1346A>G		intron_variant	Intron 2 of 4			ENSP00000504769.1

Frequencies

GnomAD3 genomes AF: 0.614 AC: 93177 AN: 151758 Hom.: 29758 Cov.: 31

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.562

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

GnomAD4 genome AF: 0.614 AC: 93259 AN: 151876 Hom.: 29788 Cov.: 31 AF XY: 0.610 AC XY: 45265 AN XY: 74210

African (AFR) AF: 0.783 AC: 32448 AN: 41444

American (AMR) AF: 0.464 AC: 7064 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1485 AN: 3468

East Asian (EAS) AF: 0.381 AC: 1959 AN: 5146

South Asian (SAS) AF: 0.547 AC: 2635 AN: 4814

European-Finnish (FIN) AF: 0.633 AC: 6670 AN: 10542

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39080 AN: 67908

Other (OTH) AF: 0.562 AC: 1185 AN: 2108

Alfa AF: 0.448 Hom.: 1145

Bravo AF: 0.607

Asia WGS AF: 0.472 AC: 1639 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.12
DANN	Benign	0.63
PhyloP100		-2.0
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: rs1989457; hg19: chr19-41852115;