chr18-31591133-G-T

Variant names:

• chr18-31591133-G-T
• rs566196517
• ENST00000649620.1:c.-1-769G>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BS2_Supporting

The ENST00000649620.1(TTR):​c.-1-769G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 135,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.00053 (0 hom., cov: 30)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0120

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 18-31591133-G-T is Benign according to our data. Variant chr18-31591133-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3771493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 72 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000649620.1	c.-1-769G>T		intron_variant	Intron 2 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.-27-1763G>T		intron_variant	Intron 1 of 3	5		ENSP00000477599.2
TTR	ENST00000613781.2	c.-1-769G>T		intron_variant	Intron 1 of 1	5		ENSP00000479174.2
TTR	ENST00000676075.1	c.-1-769G>T		intron_variant	Intron 1 of 1			ENSP00000502027.1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 72 AN: 135060 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000234

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.000214

Gnomad OTH AF: 0.000556

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

GnomAD4 genome AF: 0.000533 AC: 72 AN: 135108 Hom.: 0 Cov.: 30 AF XY: 0.000727 AC XY: 47 AN XY: 64646

Gnomad4 AFR AF: 0.0000297

Gnomad4 AMR AF: 0.000234

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000214

Gnomad4 OTH AF: 0.000550

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000170

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTR: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.46
DANN	Benign	0.70

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs566196517; hg19: chr18-29171096;