rs1667254

Variant names:

• chr18-31606165-C-T
• rs1667254
• ENST00000858991.1:c.*2094C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000858991.1(TTR):​c.*2094C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 151,860 control chromosomes in the GnomAD database, including 8,706 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 0.34 (8706 hom., cov: 31)
• Consequence: TTR ENST00000858991.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.937
• Publications: 8 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 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

ENSG00000294516 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000858991.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	ENST00000858991.1		c.*2094C>T		3_prime_UTR	Exon 5 of 5	ENSP00000529050.1
	ENSG00000294516	ENST00000724044.1		n.285+1208G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51279 AN: 151742 Hom.: 8696 Cov.: 31

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.369

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.338 AC: 51331 AN: 151860 Hom.: 8706 Cov.: 31 AF XY: 0.335 AC XY: 24877 AN XY: 74192

African (AFR) AF: 0.341 AC: 14106 AN: 41394

American (AMR) AF: 0.341 AC: 5206 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1361 AN: 3468

East Asian (EAS) AF: 0.324 AC: 1668 AN: 5156

South Asian (SAS) AF: 0.375 AC: 1804 AN: 4812

European-Finnish (FIN) AF: 0.257 AC: 2703 AN: 10526

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23240 AN: 67946

Other (OTH) AF: 0.374 AC: 787 AN: 2104

Alfa AF: 0.350 Hom.: 16360

Bravo AF: 0.343

Asia WGS AF: 0.372 AC: 1299 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.40
DANN	Benign	0.39
PhyloP100		-0.94

Splicing

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

Other links and lift over

dbSNP: rs1667254; hg19: chr18-29186128;