rs1616887

Positions:

• chr18-31580789-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000649620.1(TTR):​c.-101-5013A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 152,004 control chromosomes in the GnomAD database, including 24,412 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 0.54 (24412 hom., cov: 31)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 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.-27-12107A>G		intron_variant		5
TTR	ENST00000613781.2	c.-2+4621A>G		intron_variant		5
TTR	ENST00000649620.1	c.-101-5013A>G		intron_variant				P1
TTR	ENST00000676075.1	c.-2+4518A>G		intron_variant

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81305 AN: 151886 Hom.: 24340 Cov.: 31

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.528

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

GnomAD4 genome AF: 0.536 AC: 81443 AN: 152004 Hom.: 24412 Cov.: 31 AF XY: 0.530 AC XY: 39352 AN XY: 74304

Gnomad4 AFR AF: 0.827

Gnomad4 AMR AF: 0.513

Gnomad4 ASJ AF: 0.451

Gnomad4 EAS AF: 0.447

Gnomad4 SAS AF: 0.439

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.531

Alfa AF: 0.444 Hom.: 7570

Bravo AF: 0.564

Asia WGS AF: 0.482 AC: 1682 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.14
DANN	Benign	0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1616887; hg19: chr18-29160752;