rs1667234

Variant names:

• chr18-31568851-G-A
• rs1667234
• ENST00000649620.1:c.-102+11720G>A

Variant summary

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

The ENST00000649620.1(TTR):​c.-102+11720G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 151,940 control chromosomes in the GnomAD database, including 31,519 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 0.63 (31519 hom., cov: 31)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 2 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.896 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
TTR	ENST00000649620.1	c.-102+11720G>A		intron_variant	Intron 1 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.-28+11720G>A		intron_variant	Intron 1 of 3	5		ENSP00000477599.2

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95805 AN: 151822 Hom.: 31458 Cov.: 31

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.697

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.917

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.619

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

GnomAD4 genome AF: 0.631 AC: 95932 AN: 151940 Hom.: 31519 Cov.: 31 AF XY: 0.633 AC XY: 46958 AN XY: 74240

African (AFR) AF: 0.783 AC: 32466 AN: 41468

American (AMR) AF: 0.697 AC: 10651 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1988 AN: 3470

East Asian (EAS) AF: 0.918 AC: 4742 AN: 5168

South Asian (SAS) AF: 0.547 AC: 2630 AN: 4808

European-Finnish (FIN) AF: 0.503 AC: 5288 AN: 10522

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36216 AN: 67910

Other (OTH) AF: 0.623 AC: 1317 AN: 2114

Alfa AF: 0.556 Hom.: 12245

Bravo AF: 0.660

Asia WGS AF: 0.745 AC: 2591 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.28
DANN	Benign	0.62
PhyloP100		-1.2

Splicing

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

Other links and lift over

dbSNP: rs1667234; hg19: chr18-29148814;