rs1667250

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000371.4(TTR):​c.337-1375C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 152,078 control chromosomes in the GnomAD database, including 263 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 0.036 ( 263 hom., cov: 32)
Exomes 𝑓: 0.021 ( 0 hom. )

Consequence

TTR
NM_000371.4 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.980
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 Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.94).
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTRNM_000371.4 linkc.337-1375C>T intron_variant Intron 3 of 3 ENST00000237014.8 NP_000362.1 P02766E9KL36
LOC124904277XR_007066326.1 linkn.129-1498G>A intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTRENST00000237014.8 linkc.337-1375C>T intron_variant Intron 3 of 3 1 NM_000371.4 ENSP00000237014.4 P02766
TTRENST00000649620.1 linkc.337-1375C>T intron_variant Intron 5 of 5 ENSP00000497927.1 P02766
TTRENST00000610404.5 linkc.241-1375C>T intron_variant Intron 3 of 3 5 ENSP00000477599.2 A0A087WT59

Frequencies

GnomAD3 genomes
AF:
0.0362
AC:
5492
AN:
151864
Hom.:
259
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0921
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0583
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.0267
Gnomad SAS
AF:
0.114
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000853
Gnomad OTH
AF:
0.0258
GnomAD4 exome
AF:
0.0208
AC:
2
AN:
96
Hom.:
0
Cov.:
0
AF XY:
0.0278
AC XY:
2
AN XY:
72
show subpopulations
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.500
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0128
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0364
AC:
5527
AN:
151982
Hom.:
263
Cov.:
32
AF XY:
0.0373
AC XY:
2769
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.0925
Gnomad4 AMR
AF:
0.0584
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.0265
Gnomad4 SAS
AF:
0.115
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000853
Gnomad4 OTH
AF:
0.0279
Alfa
AF:
0.0195
Hom.:
17
Bravo
AF:
0.0415
Asia WGS
AF:
0.115
AC:
403
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.94
CADD
Benign
1.1
DANN
Benign
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs1667250; hg19: chr18-29177156; API