1-91712490-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003243.5(TGFBR3):ā€‹c.1919T>Gā€‹(p.Phe640Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TGFBR3
NM_003243.5 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.65
Variant links:
Genes affected
TGFBR3 (HGNC:11774): (transforming growth factor beta receptor 3) This locus encodes the transforming growth factor (TGF)-beta type III receptor. The encoded receptor is a membrane proteoglycan that often functions as a co-receptor with other TGF-beta receptor superfamily members. Ectodomain shedding produces soluble TGFBR3, which may inhibit TGFB signaling. Decreased expression of this receptor has been observed in various cancers. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.[provided by RefSeq, Sep 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TGFBR3NM_003243.5 linkuse as main transcriptc.1919T>G p.Phe640Cys missense_variant 13/17 ENST00000212355.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TGFBR3ENST00000212355.9 linkuse as main transcriptc.1919T>G p.Phe640Cys missense_variant 13/171 NM_003243.5 P3Q03167-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250926
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135608
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461874
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 10, 2023The c.1919T>G (p.F640C) alteration is located in exon 13 (coding exon 12) of the TGFBR3 gene. This alteration results from a T to G substitution at nucleotide position 1919, causing the phenylalanine (F) at amino acid position 640 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.85
D;.;D;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.92
D;.;.;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Uncertain
0.35
D
MutationAssessor
Uncertain
2.5
M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-3.4
D;D;D;D
REVEL
Pathogenic
0.75
Sift
Uncertain
0.013
D;D;D;D
Sift4G
Benign
0.098
T;T;T;T
Polyphen
1.0
D;D;D;D
Vest4
0.87
MutPred
0.66
Gain of catalytic residue at F640 (P = 0.0722);.;Gain of catalytic residue at F640 (P = 0.0722);.;
MVP
0.97
MPC
1.0
ClinPred
0.98
D
GERP RS
6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.31
gMVP
0.74

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: rs1426545242; hg19: chr1-92178047; API