rs723744

Positions:

• chr18-31592513-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000371.4(TTR):​c.70-383G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 152,044 control chromosomes in the GnomAD database, including 11,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.37 (11008 hom., cov: 32)
• Consequence: TTR NM_000371.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230

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=-0.9).
• BP6: Variant 18-31592513-G-T is Benign according to our data. Variant chr18-31592513-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.70-383G>T		intron_variant		ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.70-383G>T		intron_variant		1	NM_000371.4	ENSP00000237014	P1

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56898 AN: 151926 Hom.: 10996 Cov.: 32

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.395

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

GnomAD4 genome AF: 0.375 AC: 56954 AN: 152044 Hom.: 11008 Cov.: 32 AF XY: 0.371 AC XY: 27558 AN XY: 74330

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.343

Gnomad4 OTH AF: 0.398

Alfa AF: 0.358 Hom.: 12976

Bravo AF: 0.385

Asia WGS AF: 0.374 AC: 1304 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs723744; hg19: chr18-29172476;