rs58616646

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000649620.1(TTR):​c.-1-1135C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,276 control chromosomes in the GnomAD database, including 2,295 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.13 ( 2295 hom., cov: 33)

Consequence

TTR
ENST00000649620.1 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.276

Publications

2 publications found
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]
TTR Gene-Disease associations (from GenCC):
  • amyloidosis, hereditary systemic 1
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • familial amyloid neuropathy
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • hereditary ATTR amyloidosis
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • heart conduction disease
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • ATTRV122I amyloidosis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTRENST00000649620.1 linkc.-1-1135C>T intron_variant Intron 2 of 5 ENSP00000497927.1 P02766
TTRENST00000610404.5 linkc.-27-2129C>T intron_variant Intron 1 of 3 5 ENSP00000477599.2 A0A087WT59
TTRENST00000613781.2 linkc.-1-1135C>T intron_variant Intron 1 of 1 5 ENSP00000479174.2 A0A087WV45
TTRENST00000676075.1 linkc.-1-1135C>T intron_variant Intron 1 of 1 ENSP00000502027.1 A0A087WV45

Frequencies

GnomAD3 genomes
AF:
0.125
AC:
19011
AN:
152158
Hom.:
2284
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.314
Gnomad AMI
AF:
0.0515
Gnomad AMR
AF:
0.129
Gnomad ASJ
AF:
0.0498
Gnomad EAS
AF:
0.0748
Gnomad SAS
AF:
0.0384
Gnomad FIN
AF:
0.0256
Gnomad MID
AF:
0.0728
Gnomad NFE
AF:
0.0401
Gnomad OTH
AF:
0.103
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.125
AC:
19064
AN:
152276
Hom.:
2295
Cov.:
33
AF XY:
0.124
AC XY:
9202
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.314
AC:
13052
AN:
41504
American (AMR)
AF:
0.130
AC:
1985
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.0498
AC:
173
AN:
3472
East Asian (EAS)
AF:
0.0750
AC:
389
AN:
5186
South Asian (SAS)
AF:
0.0383
AC:
185
AN:
4834
European-Finnish (FIN)
AF:
0.0256
AC:
272
AN:
10620
Middle Eastern (MID)
AF:
0.0714
AC:
21
AN:
294
European-Non Finnish (NFE)
AF:
0.0401
AC:
2725
AN:
68034
Other (OTH)
AF:
0.102
AC:
215
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
751
1502
2252
3003
3754
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
180
360
540
720
900
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.103
Hom.:
199
Bravo
AF:
0.144
Asia WGS
AF:
0.0710
AC:
248
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
0.38
DANN
Benign
0.27
PhyloP100
-0.28

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs58616646; hg19: chr18-29170730; API