rs1551005

Variant names:

• chr18-31591727-G-A
• rs1551005
• ENST00000649620.1:c.-1-175G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-31591727-G-A
• chr18-31591727-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000649620.1(TTR):​c.-1-175G>A variant causes a intron change. The variant allele was found at a frequency of 0.00000195 in 511,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.72
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.-176G>A		upstream_gene_variant		ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.-176G>A		upstream_gene_variant		1	NM_000371.4	ENSP00000237014.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000195 AC: 1 AN: 511822 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 273508

African (AFR) AF: 0.00 AC: 0 AN: 14706

American (AMR) AF: 0.00 AC: 0 AN: 31380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17276

East Asian (EAS) AF: 0.0000322 AC: 1 AN: 31016

South Asian (SAS) AF: 0.00 AC: 0 AN: 54956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2224

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 297750

Other (OTH) AF: 0.00 AC: 0 AN: 28458

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.95
PhyloP100		4.7
PromoterAI		-0.0076	Neutral

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

Other links and lift over

dbSNP: rs1551005; hg19: chr18-29171690;