18-31593011-A-G
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5
The NM_000371.4(TTR):c.185A>G(p.Glu62Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E62D) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
TTR
NM_000371.4 missense
NM_000371.4 missense
Scores
7
5
7
Clinical Significance
Conservation
PhyloP100: 4.26
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a strand (size 7) in uniprot entity TTHY_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_000371.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr18-31593012-G-T is described in Lovd as [Pathogenic].
PP5
Variant 18-31593011-A-G is Pathogenic according to our data. Variant chr18-31593011-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13428.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-31593011-A-G is described in UniProt as null. Variant chr18-31593011-A-G is described in UniProt as null. Variant chr18-31593011-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTR | NM_000371.4 | c.185A>G | p.Glu62Gly | missense_variant | 2/4 | ENST00000237014.8 | NP_000362.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTR | ENST00000237014.8 | c.185A>G | p.Glu62Gly | missense_variant | 2/4 | 1 | NM_000371.4 | ENSP00000237014.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Amyloidosis, hereditary systemic 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1992 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;.
MutationTaster
Benign
A
PrimateAI
Benign
T
PROVEAN
Uncertain
.;D;.;.
REVEL
Pathogenic
Sift
Benign
.;D;.;.
Sift4G
Benign
.;T;D;D
Polyphen
B;B;.;.
Vest4
0.48, 0.63, 0.74
MutPred
Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP
1.0
MPC
1.1
ClinPred
D
GERP RS
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