rs3764479

Variant names:

• chr18-31589862-A-G
• rs3764479
• ENST00000649620.1:c.-1-2040A>G

Variant summary

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

The ENST00000649620.1(TTR):​c.-1-2040A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 152,094 control chromosomes in the GnomAD database, including 7,136 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 0.30 (7136 hom., cov: 32)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.231
• Publications: 9 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.339 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.-1-2040A>G		intron_variant	Intron 2 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.-27-3034A>G		intron_variant	Intron 1 of 3	5		ENSP00000477599.2
TTR	ENST00000613781.2	c.-1-2040A>G		intron_variant	Intron 1 of 1	5		ENSP00000479174.2
TTR	ENST00000676075.1	c.-1-2040A>G		intron_variant	Intron 1 of 1			ENSP00000502027.1

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45719 AN: 151976 Hom.: 7133 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.342

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

GnomAD4 genome AF: 0.301 AC: 45743 AN: 152094 Hom.: 7136 Cov.: 32 AF XY: 0.297 AC XY: 22069 AN XY: 74342

African (AFR) AF: 0.244 AC: 10125 AN: 41506

American (AMR) AF: 0.281 AC: 4296 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1364 AN: 3470

East Asian (EAS) AF: 0.300 AC: 1553 AN: 5176

South Asian (SAS) AF: 0.260 AC: 1252 AN: 4816

European-Finnish (FIN) AF: 0.256 AC: 2703 AN: 10562

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23271 AN: 67970

Other (OTH) AF: 0.345 AC: 727 AN: 2110

Alfa AF: 0.312 Hom.: 2848

Bravo AF: 0.301

Asia WGS AF: 0.254 AC: 883 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.7
DANN	Benign	0.52
PhyloP100		0.23

Splicing

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

Other links and lift over

dbSNP: rs3764479; hg19: chr18-29169825;