18-31592944-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000371.4(TTR):ā€‹c.118G>Cā€‹(p.Val40Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V40I) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

9
8
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.59
Variant links:
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 8 ACMG points.

PM1
In a chain Transthyretin (size 126) in uniprot entity TTHY_HUMAN there are 141 pathogenic changes around while only 6 benign (96%) 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 chr18-31592944-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTRNM_000371.4 linkc.118G>C p.Val40Leu missense_variant Exon 2 of 4 ENST00000237014.8 NP_000362.1 P02766E9KL36

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTRENST00000237014.8 linkc.118G>C p.Val40Leu missense_variant Exon 2 of 4 1 NM_000371.4 ENSP00000237014.4 P02766

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251466
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
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:
1461820
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
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.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.29
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;D;T;.
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
.;D;D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.88
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H;.;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-1.7
.;N;.;.
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0050
.;D;.;.
Sift4G
Uncertain
0.028
.;D;D;D
Polyphen
1.0
D;D;.;.
Vest4
0.71, 0.69, 0.61
MutPred
0.61
Loss of methylation at K35 (P = 0.0865);Loss of methylation at K35 (P = 0.0865);Loss of methylation at K35 (P = 0.0865);Loss of methylation at K35 (P = 0.0865);
MVP
1.0
MPC
1.3
ClinPred
0.98
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.87
gMVP
0.96

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: rs121918093; hg19: chr18-29172907; API