rs3764479

Positions:

• chr18-31589862-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.30 (7136 hom., cov: 32)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.231

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-31589862-A-G is Benign according to our data. Variant chr18-31589862-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000610404.5	c.-27-3034A>G		intron_variant		5
TTR	ENST00000613781.2	c.-1-2040A>G		intron_variant		5
TTR	ENST00000649620.1	c.-1-2040A>G		intron_variant				P1
TTR	ENST00000676075.1	c.-1-2040A>G		intron_variant

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

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.300

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.345

Alfa AF: 0.307 Hom.: 1573

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3764479; hg19: chr18-29169825;