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rs1800471

Variant summary

Our verdict is Benign. Variant got -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. 10/16 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 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:2

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]

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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=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/exons MANE UniProt
TGFB1NM_000660.7 linkuse as main transcriptc.74G>C p.Arg25Pro missense_variant 1/7 ENST00000221930.6
TGFB1XM_011527242.3 linkuse as main transcriptc.74G>C p.Arg25Pro missense_variant 1/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TGFB1ENST00000221930.6 linkuse as main transcriptc.74G>C p.Arg25Pro missense_variant 1/71 NM_000660.7 P1
TMEM91ENST00000539627.5 linkuse as main transcriptc.-30+1769C>G intron_variant 1
TGFB1ENST00000600196.2 linkuse as main transcriptc.74G>C p.Arg25Pro missense_variant 1/65
TGFB1ENST00000677934.1 linkuse as main transcriptc.74G>C p.Arg25Pro missense_variant 1/5

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
GnomAD3 exomes
AF:
0.0565
AC:
8035
AN:
142282
Hom.:
245
AF XY:
0.0592
AC XY:
4571
AN XY:
77192
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 SAS exome
AF:
0.0783
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
Gnomad4 AMR exome
AF:
0.0369
Gnomad4 ASJ exome
AF:
0.0412
Gnomad4 EAS exome
AF:
0.000390
Gnomad4 SAS exome
AF:
0.0759
Gnomad4 FIN exome
AF:
0.0394
Gnomad4 NFE exome
AF:
0.0777
Gnomad4 OTH exome
AF:
0.0662
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
Gnomad4 AMR
AF:
0.0407
Gnomad4 ASJ
AF:
0.0435
Gnomad4 EAS
AF:
0.00136
Gnomad4 SAS
AF:
0.0761
Gnomad4 FIN
AF:
0.0310
Gnomad4 NFE
AF:
0.0775
Gnomad4 OTH
AF:
0.0544
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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -

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
MutationTaster
Benign
1.0
D;D
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

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; API