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rs1800470

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000660.7(TGFB1):c.29C>T(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,527,994 control chromosomes in the GnomAD database, including 280,580 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P10R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.59 ( 26724 hom., cov: 33)
Exomes 𝑓: 0.61 ( 253856 hom. )

Consequence

TGFB1
NM_000660.7 missense

Scores

2
14

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:2

Conservation

PhyloP100: 0.760
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=5.7511124E-6).
BP6
Variant 19-41353016-G-A is Benign according to our data. Variant chr19-41353016-G-A is described in ClinVar as [Benign]. Clinvar id is 12534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41353016-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TGFB1NM_000660.7 linkuse as main transcriptc.29C>T p.Pro10Leu missense_variant 1/7 ENST00000221930.6
TGFB1XM_011527242.3 linkuse as main transcriptc.29C>T p.Pro10Leu missense_variant 1/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TGFB1ENST00000221930.6 linkuse as main transcriptc.29C>T p.Pro10Leu missense_variant 1/71 NM_000660.7 P1
TMEM91ENST00000539627.5 linkuse as main transcriptc.-30+1814G>A intron_variant 1
TGFB1ENST00000600196.2 linkuse as main transcriptc.29C>T p.Pro10Leu missense_variant 1/65
TGFB1ENST00000677934.1 linkuse as main transcriptc.29C>T p.Pro10Leu missense_variant 1/5

Frequencies

GnomAD3 genomes
AF:
0.589
AC:
89408
AN:
151872
Hom.:
26723
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.575
Gnomad AMI
AF:
0.785
Gnomad AMR
AF:
0.518
Gnomad ASJ
AF:
0.501
Gnomad EAS
AF:
0.443
Gnomad SAS
AF:
0.544
Gnomad FIN
AF:
0.714
Gnomad MID
AF:
0.538
Gnomad NFE
AF:
0.611
Gnomad OTH
AF:
0.563
GnomAD3 exomes
AF:
0.552
AC:
71740
AN:
129938
Hom.:
19769
AF XY:
0.554
AC XY:
39248
AN XY:
70790
show subpopulations
Gnomad AFR exome
AF:
0.567
Gnomad AMR exome
AF:
0.477
Gnomad ASJ exome
AF:
0.494
Gnomad EAS exome
AF:
0.449
Gnomad SAS exome
AF:
0.537
Gnomad FIN exome
AF:
0.707
Gnomad NFE exome
AF:
0.604
Gnomad OTH exome
AF:
0.559
GnomAD4 exome
AF:
0.606
AC:
834062
AN:
1376004
Hom.:
253856
Cov.:
55
AF XY:
0.603
AC XY:
409363
AN XY:
678490
show subpopulations
Gnomad4 AFR exome
AF:
0.565
Gnomad4 AMR exome
AF:
0.482
Gnomad4 ASJ exome
AF:
0.491
Gnomad4 EAS exome
AF:
0.479
Gnomad4 SAS exome
AF:
0.538
Gnomad4 FIN exome
AF:
0.712
Gnomad4 NFE exome
AF:
0.622
Gnomad4 OTH exome
AF:
0.581
GnomAD4 genome
AF:
0.588
AC:
89439
AN:
151990
Hom.:
26724
Cov.:
33
AF XY:
0.589
AC XY:
43749
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.574
Gnomad4 AMR
AF:
0.517
Gnomad4 ASJ
AF:
0.501
Gnomad4 EAS
AF:
0.444
Gnomad4 SAS
AF:
0.544
Gnomad4 FIN
AF:
0.714
Gnomad4 NFE
AF:
0.611
Gnomad4 OTH
AF:
0.559
Alfa
AF:
0.504
Hom.:
2560
Bravo
AF:
0.573
TwinsUK
AF:
0.629
AC:
2334
ALSPAC
AF:
0.622
AC:
2398
ExAC
AF:
0.488
AC:
27708

ClinVar

Significance: Benign
Submissions summary: Benign:8Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJan 24, 2024This variant is classified as Benign based on local population frequency. This variant was detected in 78% of patients studied by a panel of primary immunodeficiencies. Number of patients: 74. Only high quality variants are reported. -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Inflammatory bowel disease, immunodeficiency, and encephalopathy Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Meckel syndrome, type 10 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 11, 2021- -
Diaphyseal dysplasia Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
Cystic fibrosis Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 15, 2008- -
Breast cancer, invasive, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 15, 2008- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.70
T
BayesDel_noAF
Benign
-0.64
Cadd
Benign
20
Dann
Uncertain
0.98
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.12
FATHMM_MKL
Benign
0.61
D
LIST_S2
Benign
0.50
T
MetaRNN
Benign
0.0000058
T
MetaSVM
Benign
-0.95
T
MutationTaster
Benign
4.1e-11
P;P
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
0.34
N
REVEL
Benign
0.017
Sift
Benign
0.83
T
Sift4G
Benign
0.18
T
Vest4
0.098
MPC
0.67
ClinPred
0.0082
T
GERP RS
1.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

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

Other links and lift over

dbSNP: rs1800470; hg19: chr19-41858921; COSMIC: COSV54683540; COSMIC: COSV54683540; API