rs3764477

Variant names:

• chr18-31590746-G-A
• rs3764477
• ENST00000649620.1:c.-1-1156G>A

Variant summary

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

The ENST00000649620.1(TTR):​c.-1-1156G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0409 in 152,214 control chromosomes in the GnomAD database, including 178 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 0.041 (178 hom., cov: 33)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.408
• Publications: 3 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0947 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.-1-1156G>A		intron_variant	Intron 2 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.-27-2150G>A		intron_variant	Intron 1 of 3	5		ENSP00000477599.2
TTR	ENST00000613781.2	c.-1-1156G>A		intron_variant	Intron 1 of 1	5		ENSP00000479174.2
TTR	ENST00000676075.1	c.-1-1156G>A		intron_variant	Intron 1 of 1			ENSP00000502027.1

Frequencies

GnomAD3 genomes AF: 0.0409 AC: 6221 AN: 152096 Hom.: 175 Cov.: 33

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0983

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.0724

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.0257

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0391

Gnomad OTH AF: 0.0468

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

GnomAD4 genome AF: 0.0409 AC: 6229 AN: 152214 Hom.: 178 Cov.: 33 AF XY: 0.0410 AC XY: 3052 AN XY: 74400

African (AFR) AF: 0.0233 AC: 970 AN: 41544

American (AMR) AF: 0.0988 AC: 1511 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3468

East Asian (EAS) AF: 0.0726 AC: 375 AN: 5166

South Asian (SAS) AF: 0.0218 AC: 105 AN: 4818

European-Finnish (FIN) AF: 0.0257 AC: 272 AN: 10588

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0391 AC: 2660 AN: 68018

Other (OTH) AF: 0.0463 AC: 98 AN: 2116

Alfa AF: 0.0459 Hom.: 24

Bravo AF: 0.0471

Asia WGS AF: 0.0480 AC: 166 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.32
PhyloP100		-0.41

Splicing

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

Other links and lift over

dbSNP: rs3764477; hg19: chr18-29170709;