rs1800471

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000660.7(TGFB1):​c.74G>C​(p.Arg25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0711 in 1,543,868 control chromosomes in the GnomAD database, including 4,202 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.063 ( 356 hom., cov: 32)
Exomes 𝑓: 0.072 ( 3846 hom. )

Consequence

TGFB1
NM_000660.7 missense

Scores

3
13

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.754
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.002168864).
BP6
Variant 19-41352971-C-G is Benign according to our data. Variant chr19-41352971-C-G is described in ClinVar as [Benign]. Clinvar id is 38902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41352971-C-G is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0757 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TGFB1NM_000660.7 linkc.74G>C p.Arg25Pro missense_variant Exon 1 of 7 ENST00000221930.6 NP_000651.3 P01137A0A499FJK2
TGFB1XM_011527242.3 linkc.74G>C p.Arg25Pro missense_variant Exon 1 of 7 XP_011525544.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TGFB1ENST00000221930.6 linkc.74G>C p.Arg25Pro missense_variant Exon 1 of 7 1 NM_000660.7 ENSP00000221930.4 A0A499FJK2

Frequencies

GnomAD3 genomes
AF:
0.0630
AC:
9580
AN:
152132
Hom.:
354
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0647
Gnomad AMI
AF:
0.0307
Gnomad AMR
AF:
0.0407
Gnomad ASJ
AF:
0.0435
Gnomad EAS
AF:
0.00135
Gnomad SAS
AF:
0.0750
Gnomad FIN
AF:
0.0310
Gnomad MID
AF:
0.0538
Gnomad NFE
AF:
0.0775
Gnomad OTH
AF:
0.0550
GnomAD2 exomes
AF:
0.0565
AC:
8035
AN:
142282
AF XY:
0.0592
show subpopulations
Gnomad AFR exome
AF:
0.0649
Gnomad AMR exome
AF:
0.0341
Gnomad ASJ exome
AF:
0.0401
Gnomad EAS exome
AF:
0.000818
Gnomad FIN exome
AF:
0.0347
Gnomad NFE exome
AF:
0.0732
Gnomad OTH exome
AF:
0.0571
GnomAD4 exome
AF:
0.0719
AC:
100121
AN:
1391618
Hom.:
3846
Cov.:
33
AF XY:
0.0717
AC XY:
49252
AN XY:
687184
show subpopulations
Gnomad4 AFR exome
AF:
0.0623
AC:
1972
AN:
31654
Gnomad4 AMR exome
AF:
0.0369
AC:
1324
AN:
35926
Gnomad4 ASJ exome
AF:
0.0412
AC:
1038
AN:
25166
Gnomad4 EAS exome
AF:
0.000390
AC:
14
AN:
35914
Gnomad4 SAS exome
AF:
0.0759
AC:
6049
AN:
79676
Gnomad4 FIN exome
AF:
0.0394
AC:
1542
AN:
39170
Gnomad4 NFE exome
AF:
0.0777
AC:
83964
AN:
1080410
Gnomad4 Remaining exome
AF:
0.0662
AC:
3839
AN:
58016
Heterozygous variant carriers
0
5779
11558
17336
23115
28894
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
3140
6280
9420
12560
15700
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0630
AC:
9586
AN:
152250
Hom.:
356
Cov.:
32
AF XY:
0.0607
AC XY:
4518
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.0645
AC:
0.0644913
AN:
0.0644913
Gnomad4 AMR
AF:
0.0407
AC:
0.0407243
AN:
0.0407243
Gnomad4 ASJ
AF:
0.0435
AC:
0.0434908
AN:
0.0434908
Gnomad4 EAS
AF:
0.00136
AC:
0.00135764
AN:
0.00135764
Gnomad4 SAS
AF:
0.0761
AC:
0.0760779
AN:
0.0760779
Gnomad4 FIN
AF:
0.0310
AC:
0.0309793
AN:
0.0309793
Gnomad4 NFE
AF:
0.0775
AC:
0.0774807
AN:
0.0774807
Gnomad4 OTH
AF:
0.0544
AC:
0.0543992
AN:
0.0543992
Heterozygous variant carriers
0
471
942
1412
1883
2354
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
116
232
348
464
580
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0554
Hom.:
95
Bravo
AF:
0.0629
TwinsUK
AF:
0.0798
AC:
296
ALSPAC
AF:
0.0838
AC:
323
ESP6500AA
AF:
0.0454
AC:
187
ESP6500EA
AF:
0.0491
AC:
396
ExAC
AF:
0.0264
AC:
2615
Asia WGS
AF:
0.0300
AC:
104
AN:
3474

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
21
DANN
Uncertain
0.97
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.15
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.63
T
MetaRNN
Benign
0.0022
T
MetaSVM
Benign
-1.1
T
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.50
N
REVEL
Benign
0.067
Sift
Benign
0.25
T
Sift4G
Benign
0.28
T
Vest4
0.16
MPC
2.0
ClinPred
0.018
T
GERP RS
2.8
Mutation Taster
=89/11
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

Publications

LitVar

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

Other links and lift over

dbSNP: rs1800471; hg19: chr19-41858876; COSMIC: COSV107288876; COSMIC: COSV107288876; API