19-41337556-T-C

Variant names:

• chr19-41337556-T-C
• rs11466345
• NM_000660.7:c.860+4327A>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.860+4327A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,034 control chromosomes in the GnomAD database, including 1,294 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 0.12 (1294 hom., cov: 31)
• Consequence: TGFB1 NM_000660.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.68
• Publications: 26 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 (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.860+4327A>G		intron_variant	Intron 5 of 6	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.863+4327A>G		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+4327A>G		intron_variant	Intron 5 of 6	1	NM_000660.7	ENSP00000221930.4
TGFB1	ENST00000600196.2	c.712+4614A>G		intron_variant	Intron 4 of 5	5		ENSP00000504008.1
TGFB1	ENST00000677934.1	c.635-5275A>G		intron_variant	Intron 3 of 4			ENSP00000504769.1
TGFB1	ENST00000598758.5	n.148+4327A>G		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18379 AN: 151916 Hom.: 1285 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.0942

Gnomad ASJ AF: 0.0912

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.0919

Gnomad FIN AF: 0.0884

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.129

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

GnomAD4 genome AF: 0.121 AC: 18433 AN: 152034 Hom.: 1294 Cov.: 31 AF XY: 0.120 AC XY: 8902 AN XY: 74348

African (AFR) AF: 0.176 AC: 7291 AN: 41454

American (AMR) AF: 0.0939 AC: 1433 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0912 AC: 316 AN: 3466

East Asian (EAS) AF: 0.267 AC: 1376 AN: 5162

South Asian (SAS) AF: 0.0918 AC: 443 AN: 4828

European-Finnish (FIN) AF: 0.0884 AC: 936 AN: 10588

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0906 AC: 6160 AN: 67972

Other (OTH) AF: 0.129 AC: 272 AN: 2102

Alfa AF: 0.117 Hom.: 413

Bravo AF: 0.126

Asia WGS AF: 0.197 AC: 683 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	0.33
DANN	Benign	0.26
PhyloP100		-4.7
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: rs11466345; hg19: chr19-41843461;