rs747857

Variant names:

• chr19-41331842-G-A
• rs747857
• NM_000660.7:c.1014+286C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-41331842-G-A
• chr19-41331842-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000660.7(TGFB1):​c.1014+286C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0633 in 150,954 control chromosomes in the GnomAD database, including 830 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.063 (830 hom., cov: 28)
• Consequence: TGFB1 NM_000660.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.370
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-41331842-G-A is Benign according to our data. Variant chr19-41331842-G-A is described in ClinVar as Benign. ClinVar VariationId is 1230600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB1	NM_000660.7	c.1014+286C>T		intron_variant	Intron 6 of 6	ENST00000221930.6	NP_000651.3
TGFB1	XM_011527242.3	c.1017+286C>T		intron_variant	Intron 6 of 6		XP_011525544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB1	ENST00000221930.6	c.1014+286C>T		intron_variant	Intron 6 of 6	1	NM_000660.7	ENSP00000221930.4
TGFB1	ENST00000600196.2	c.954+198C>T		intron_variant	Intron 5 of 5	5		ENSP00000504008.1
TGFB1	ENST00000677934.1	c.788+286C>T		intron_variant	Intron 4 of 4			ENSP00000504769.1
TGFB1	ENST00000598758.5	n.302+286C>T		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 9513 AN: 150834 Hom.: 817 Cov.: 28

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.0681

Gnomad SAS AF: 0.0725

Gnomad FIN AF: 0.00298

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00217

Gnomad OTH AF: 0.0506

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

GnomAD4 genome AF: 0.0633 AC: 9557 AN: 150954 Hom.: 830 Cov.: 28 AF XY: 0.0645 AC XY: 4753 AN XY: 73692

African (AFR) AF: 0.191 AC: 7840 AN: 40976

American (AMR) AF: 0.0472 AC: 710 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 22 AN: 3466

East Asian (EAS) AF: 0.0682 AC: 350 AN: 5132

South Asian (SAS) AF: 0.0727 AC: 347 AN: 4770

European-Finnish (FIN) AF: 0.00298 AC: 31 AN: 10404

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00217 AC: 147 AN: 67848

Other (OTH) AF: 0.0501 AC: 105 AN: 2096

Alfa AF: 0.0397 Hom.: 67

Bravo AF: 0.0726

Asia WGS AF: 0.0910 AC: 314 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.8
DANN	Benign	0.94
PhyloP100		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs747857; hg19: chr19-41837747;