rs8179181

chr19-41332301-G-Achr19-41332301-G-Cchr19-41332301-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000660.7(TGFB1):c.861-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,608,868 control chromosomes in the GnomAD database, including 40,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2707 hom., cov: 31)
  • Exomes 𝑓: 0.22 (37398 hom.)
• Consequence: TGFB1 NM_000660.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.512

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-41332301-G-A is Benign according to our data. Variant chr19-41332301-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB1	NM_000660.7	c.861-20C>T		intron_variant		ENST00000221930.6
TGFB1	XM_011527242.3	c.864-20C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB1	ENST00000221930.6	c.861-20C>T		intron_variant		1	NM_000660.7	P1
TGFB1	ENST00000600196.2	c.713-20C>T		intron_variant		5
TGFB1	ENST00000677934.1	c.635-20C>T		intron_variant
TGFB1	ENST00000598758.5	n.149-20C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24647 AN: 152020 Hom.: 2707 Cov.: 31

Gnomad AFR AF: 0.0423

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0654

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.169 AC: 41176 AN: 243806 Hom.: 4449 AF XY: 0.172 AC XY: 22726 AN XY: 132436

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.0994

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.000552

Gnomad SAS exome AF: 0.0735

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.217 AC: 315509 AN: 1456730 Hom.: 37398 Cov.: 33 AF XY: 0.213 AC XY: 154002 AN XY: 724274

Gnomad4 AFR exome AF: 0.0333

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.000379

Gnomad4 SAS exome AF: 0.0758

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.162 AC: 24647 AN: 152138 Hom.: 2707 Cov.: 31 AF XY: 0.159 AC XY: 11849 AN XY: 74354

Gnomad4 AFR AF: 0.0422

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0661

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.160

Alfa AF: 0.205 Hom.: 2237

Bravo AF: 0.147

Asia WGS AF: 0.0360 AC: 127 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Inflammatory bowel disease, immunodeficiency, and encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Cystic fibrosis;C0011989:Diaphyseal dysplasia;C4748708:Inflammatory bowel disease, immunodeficiency, and encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 30, 2021

- -

Diaphyseal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	13
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs8179181; hg19: chr19-41838206; COSMIC: COSV55726545;