chr18-31592074-A-G

Position:

• chr18-31592074-A-G

Variant summary

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

The NM_000371.4(TTR):​c.69+103A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,121,304 control chromosomes in the GnomAD database, including 856 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 0.021 (108 hom., cov: 33)
  • Exomes 𝑓: 0.015 (748 hom.)
• Consequence: TTR NM_000371.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250

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=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.69+103A>G		intron_variant		ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.69+103A>G		intron_variant		1	NM_000371.4	P1

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3164 AN: 152166 Hom.: 108 Cov.: 33

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0270

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.0150 AC: 14500 AN: 969020 Hom.: 748 AF XY: 0.0179 AC XY: 8996 AN XY: 502868

Gnomad4 AFR exome AF: 0.0358

Gnomad4 AMR exome AF: 0.0733

Gnomad4 ASJ exome AF: 0.000744

Gnomad4 EAS exome AF: 0.0298

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000481

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0209 AC: 3180 AN: 152284 Hom.: 108 Cov.: 33 AF XY: 0.0226 AC XY: 1682 AN XY: 74470

Gnomad4 AFR AF: 0.0369

Gnomad4 AMR AF: 0.0559

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0268

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0108 Hom.: 3

Bravo AF: 0.0243

Asia WGS AF: 0.109 AC: 382 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.1
DANN	Benign	0.83

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: rs9304103; hg19: chr18-29172037;