rs761100949
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM1PM2_SupportingBP4_Moderate
The NM_000660.7(TGFB1):c.292G>C (p.Glu98Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,028 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E98K: Uncertain_significance (ClinVar VariationId 2969295, 1 star)
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TGFB1
NM_000660.7 missense
NM_000660.7 missense
Scores
1
16
Clinical Significance
Conservation
PhyloP100: 0.539
Publications
0 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 diseaseInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- Camurati-Engelmann disease type 1Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
- inflammatory bowel disease, immunodeficiency, and encephalopathyInheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
- cystic fibrosisInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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]
Genome browser will be placed here
new If you want to explore the variant's impact on the transcript NM_000660.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
Classification according to ACMG Germline Pathogenicity v2019
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 1 points.
PM1
UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 9 pathogenic, 3 benign rare missense variants (OR vs. background: 13.6).; ±8 AA neighbourhood: 0 pathogenic, 0 benign.
PM2
Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
BP4
Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_000660.7. You can select a different transcript below to see updated classification assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TGFB1 | TSL:1 MANE Select | c.292G>C | p.Glu98Gln | missense | Exon 1 of 7 | ENSP00000221930.4 | A0A499FJK2 | ||
| TMEM91 | TSL:1 | c.-30+1551C>G | intron | N/A | ENSP00000441900.1 | F5GWC9 | |||
| TMEM91 | c.-420C>G | 5_prime_UTR_premature_start_codon_gain | Exon 1 of 4 | ENSP00000636343.1 | Q6ZNR0-1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152128
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461028Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726814 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461028
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
726814
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33468
American (AMR)
AF:
AC:
0
AN:
44670
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26080
East Asian (EAS)
AF:
AC:
0
AN:
39690
South Asian (SAS)
AF:
AC:
0
AN:
86156
European-Finnish (FIN)
AF:
AC:
0
AN:
53178
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111674
Other (OTH)
AF:
AC:
1
AN:
60350
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
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10
<30
30-35
35-40
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Age
GnomAD4 genome 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74306 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
1
AN:
152128
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
74306
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
41454
American (AMR)
AF:
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5156
South Asian (SAS)
AF:
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68008
Other (OTH)
AF:
AC:
0
AN:
2092
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
TOPMed (Bravo)
AF:
AC:
1
AN:
264690
Hom.:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)
AF:
AC:
0
AN:
21310
Hom.:
Case/control cohorts
Cohort
Cases
Controls
SCHEMA
0 / 102938AF: 0
1 / 183590AF: 0.00000544692
Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).
ClinVar
ClinVar submissions
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
-
1
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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Other links and lift over
dbSNP: rs761100949 ;
hg19: chr19-41858658;