ENST00000598758.5:n.302+4866A>G

Variant names:

• chr19-41327262-T-C
• rs10417924
• ENST00000598758.5:n.302+4866A>G

Variant summary

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

The ENST00000598758.5(TGFB1):​n.302+4866A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 152,130 control chromosomes in the GnomAD database, including 56,079 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 0.86 (56079 hom., cov: 31)
• Consequence: TGFB1 ENST00000598758.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.248
• Publications: 29 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.957 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+4866A>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.855 AC: 129993 AN: 152012 Hom.: 56016 Cov.: 31

Gnomad AFR AF: 0.965

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.856

Gnomad SAS AF: 0.896

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.835

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

GnomAD4 genome AF: 0.855 AC: 130118 AN: 152130 Hom.: 56079 Cov.: 31 AF XY: 0.855 AC XY: 63593 AN XY: 74340

African (AFR) AF: 0.965 AC: 40072 AN: 41534

American (AMR) AF: 0.842 AC: 12865 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 2617 AN: 3470

East Asian (EAS) AF: 0.856 AC: 4416 AN: 5158

South Asian (SAS) AF: 0.896 AC: 4318 AN: 4820

European-Finnish (FIN) AF: 0.816 AC: 8627 AN: 10566

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.800 AC: 54411 AN: 67984

Other (OTH) AF: 0.837 AC: 1771 AN: 2116

Alfa AF: 0.807 Hom.: 96524

Bravo AF: 0.860

Asia WGS AF: 0.900 AC: 3127 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.1
DANN	Benign	0.62
PhyloP100		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

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

Other links and lift over

dbSNP: rs10417924; hg19: chr19-41833167;