rs3794884

Positions:

• chr18-31597008-T-G

Variant summary

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

The NM_000371.4(TTR):​c.337-1560T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 152,018 control chromosomes in the GnomAD database, including 8,747 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 0.34 (8745 hom., cov: 31)
  • Exomes 𝑓: 0.45 (2 hom.)
• Consequence: TTR NM_000371.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.258

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]

LOC124904277 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.337-1560T>G		intron_variant		ENST00000237014.8
LOC124904277	XR_007066326.1	n.129-1313A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.337-1560T>G		intron_variant		1	NM_000371.4	P1
TTR	ENST00000610404.5	c.241-1560T>G		intron_variant		5
TTR	ENST00000649620.1	c.337-1560T>G		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51000 AN: 151878 Hom.: 8732 Cov.: 31

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.364

GnomAD4 exome AF: 0.455 AC: 10 AN: 22 Hom.: 2 AF XY: 0.563 AC XY: 9 AN XY: 16

Gnomad4 NFE exome AF: 0.455

GnomAD4 genome AF: 0.336 AC: 51055 AN: 151996 Hom.: 8745 Cov.: 31 AF XY: 0.332 AC XY: 24630 AN XY: 74298

Gnomad4 AFR AF: 0.365

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.366

Alfa AF: 0.353 Hom.: 10496

Bravo AF: 0.341

Asia WGS AF: 0.267 AC: 928 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.2
DANN	Benign	0.59

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: rs3794884; hg19: chr18-29176971;