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GeneBe

19-41352691-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_000660.7(TGFB1):c.354C>T(p.Asn118=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

TGFB1
NM_000660.7 splice_region, synonymous

Scores

2
Splicing: ADA: 0.0001839
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.265
Variant links:
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]
TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP7
Synonymous conserved (PhyloP=0.265 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TGFB1NM_000660.7 linkuse as main transcriptc.354C>T p.Asn118= splice_region_variant, synonymous_variant 1/7 ENST00000221930.6
TGFB1XM_011527242.3 linkuse as main transcriptc.354C>T p.Asn118= splice_region_variant, synonymous_variant 1/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TGFB1ENST00000221930.6 linkuse as main transcriptc.354C>T p.Asn118= splice_region_variant, synonymous_variant 1/71 NM_000660.7 P1
TMEM91ENST00000539627.5 linkuse as main transcriptc.-30+1489G>A intron_variant 1
TGFB1ENST00000600196.2 linkuse as main transcriptc.354C>T p.Asn118= splice_region_variant, synonymous_variant 1/65
TGFB1ENST00000677934.1 linkuse as main transcriptc.354C>T p.Asn118= splice_region_variant, synonymous_variant 1/5

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeFeb 08, 2022This variant has not been reported in the literature in individuals affected with TGFB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 118 of the TGFB1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TGFB1 protein. It affects a nucleotide within the consensus splice site. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
Cadd
Benign
9.4
Dann
Benign
0.74
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00018
dbscSNV1_RF
Benign
0.046
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2038222572; hg19: chr19-41858596; API