rs145551875
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_000371.4(TTR):c.140A>C(p.Asn47Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,198 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N47S) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
TTR
NM_000371.4 missense
NM_000371.4 missense
Scores
2
8
9
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 2.00
Publications
5 publications found
Genes affected
TTR (HGNC:12405): (transthyretin) This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]
TTR Gene-Disease associations (from GenCC):
- amyloidosis, hereditary systemic 1Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
- familial amyloid neuropathyInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- hereditary ATTR amyloidosisInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- heart conduction diseaseInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- ATTRV122I amyloidosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
PM1
In a hotspot region, there are 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000371.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 108 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0149 (below the threshold of 3.09). Trascript score misZ: 1.5458 (below the threshold of 3.09). GenCC associations: The gene is linked to familial amyloid neuropathy, amyloidosis, hereditary systemic 1, ATTRV122I amyloidosis, hereditary ATTR amyloidosis, heart conduction disease.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152198
Hom.:
Cov.:
32
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 Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152198
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74344
show subpopulations
African (AFR)
AF:
AC:
1
AN:
41442
American (AMR)
AF:
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5190
South Asian (SAS)
AF:
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68032
Other (OTH)
AF:
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
DANN
Benign
DEOGEN2
Pathogenic
D;D;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;T;T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.;.
PhyloP100
PrimateAI
Benign
T
PROVEAN
Uncertain
.;D;.;.
REVEL
Uncertain
Sift
Uncertain
.;D;.;.
Sift4G
Benign
.;T;T;T
Polyphen
B;B;.;.
Vest4
0.34, 0.36, 0.34
MutPred
Gain of glycosylation at N47 (P = 0.0518);Gain of glycosylation at N47 (P = 0.0518);Gain of glycosylation at N47 (P = 0.0518);Gain of glycosylation at N47 (P = 0.0518);
MVP
0.95
MPC
0.57
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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
Publications
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