19-41349011-A-G

Variant names:

• chr19-41349011-A-G
• rs11466321
• NM_000660.7:c.356-556T>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.356-556T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 152,106 control chromosomes in the GnomAD database, including 343 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 0.062 (343 hom., cov: 32)
• Consequence: TGFB1 NM_000660.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.217
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.356-556T>C		intron_variant	Intron 1 of 6	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.356-556T>C		intron_variant	Intron 1 of 6		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.356-556T>C		intron_variant	Intron 1 of 6	1	NM_000660.7	ENSP00000221930.4
TGFB1	ENST00000600196.2	c.356-556T>C		intron_variant	Intron 1 of 5	5		ENSP00000504008.1
TGFB1	ENST00000677934.1	c.356-556T>C		intron_variant	Intron 1 of 4			ENSP00000504769.1

Frequencies

GnomAD3 genomes AF: 0.0619 AC: 9401 AN: 151988 Hom.: 341 Cov.: 32

Gnomad AFR AF: 0.0618

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0747

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0499

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

GnomAD4 genome AF: 0.0618 AC: 9407 AN: 152106 Hom.: 343 Cov.: 32 AF XY: 0.0596 AC XY: 4430 AN XY: 74348

African (AFR) AF: 0.0616 AC: 2556 AN: 41494

American (AMR) AF: 0.0397 AC: 606 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3466

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5170

South Asian (SAS) AF: 0.0758 AC: 365 AN: 4816

European-Finnish (FIN) AF: 0.0308 AC: 327 AN: 10602

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0772 AC: 5250 AN: 67996

Other (OTH) AF: 0.0494 AC: 104 AN: 2106

Alfa AF: 0.0649 Hom.: 470

Bravo AF: 0.0613

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.9
DANN	Benign	0.59
PhyloP100		0.22
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: rs11466321; hg19: chr19-41854916;