rs72922940

chr18-31590735-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.-1-1167A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 152,318 control chromosomes in the GnomAD database, including 911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.097 (911 hom., cov: 33)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.437

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=-0.87).
• BP6: Variant 18-31590735-A-G is Benign according to our data. Variant chr18-31590735-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 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.-27-2161A>G		intron_variant		5
TTR	ENST00000613781.2	c.-1-1167A>G		intron_variant		5
TTR	ENST00000649620.1	c.-1-1167A>G		intron_variant				P1
TTR	ENST00000676075.1	c.-1-1167A>G		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0974 AC: 14831 AN: 152200 Hom.: 912 Cov.: 33

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0834

Gnomad FIN AF: 0.0714

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.118

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

GnomAD4 genome AF: 0.0973 AC: 14826 AN: 152318 Hom.: 911 Cov.: 33 AF XY: 0.0951 AC XY: 7079 AN XY: 74470

Gnomad4 AFR AF: 0.0572

Gnomad4 AMR AF: 0.0999

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0836

Gnomad4 FIN AF: 0.0714

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.117

Alfa AF: 0.121 Hom.: 381

Bravo AF: 0.0980

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	2.3
Dann	Benign	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72922940; hg19: chr18-29170698;