19-41339853-C-G

Variant names:

• chr19-41339853-C-G
• rs2278422
• NM_000660.7:c.860+2030G>C

Variant summary

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

The NM_000660.7(TGFB1):​c.860+2030G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 151,824 control chromosomes in the GnomAD database, including 15,839 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 0.43 (15839 hom., cov: 31)
• Consequence: TGFB1 NM_000660.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.206
• Publications: 13 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.860+2030G>C		intron_variant	Intron 5 of 6	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.863+2030G>C		intron_variant	Intron 5 of 6		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.860+2030G>C		intron_variant	Intron 5 of 6	1	NM_000660.7	ENSP00000221930.4
TGFB1	ENST00000600196.2	c.712+2317G>C		intron_variant	Intron 4 of 5	5		ENSP00000504008.1
TGFB1	ENST00000677934.1	c.634+4894G>C		intron_variant	Intron 3 of 4			ENSP00000504769.1
TGFB1	ENST00000598758.5	n.148+2030G>C		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.435 AC: 65962 AN: 151704 Hom.: 15828 Cov.: 31

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.439

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

GnomAD4 genome AF: 0.435 AC: 66017 AN: 151824 Hom.: 15839 Cov.: 31 AF XY: 0.447 AC XY: 33185 AN XY: 74196

African (AFR) AF: 0.295 AC: 12225 AN: 41396

American (AMR) AF: 0.571 AC: 8713 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1623 AN: 3472

East Asian (EAS) AF: 0.973 AC: 5010 AN: 5150

South Asian (SAS) AF: 0.514 AC: 2477 AN: 4816

European-Finnish (FIN) AF: 0.517 AC: 5428 AN: 10508

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.432 AC: 29329 AN: 67926

Other (OTH) AF: 0.441 AC: 927 AN: 2100

Alfa AF: 0.296 Hom.: 788

Bravo AF: 0.436

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.9
DANN	Benign	0.81
PhyloP100		-0.21
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: rs2278422; hg19: chr19-41845758;