18-31591160-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000649620.1(TTR):c.-1-742A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 145,960 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: 𝑓 0.0043 (8 hom., cov: 29)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0740

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 18-31591160-A-T is Benign according to our data. Variant chr18-31591160-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 744399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 628 AD gene.

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.-27-1736A>T		intron_variant		5
TTR	ENST00000613781.2	c.-1-742A>T		intron_variant		5
TTR	ENST00000649620.1	c.-1-742A>T		intron_variant				P1
TTR	ENST00000676075.1	c.-1-742A>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 628 AN: 145884 Hom.: 8 Cov.: 29

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00556

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.000582

Gnomad EAS AF: 0.0178

Gnomad SAS AF: 0.0171

Gnomad FIN AF: 0.00328

Gnomad MID AF: 0.00671

Gnomad NFE AF: 0.00383

Gnomad OTH AF: 0.00404

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

GnomAD4 genome AF: 0.00432 AC: 630 AN: 145960 Hom.: 8 Cov.: 29 AF XY: 0.00465 AC XY: 329 AN XY: 70722

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.000582

Gnomad4 EAS AF: 0.0178

Gnomad4 SAS AF: 0.0171

Gnomad4 FIN AF: 0.00328

Gnomad4 NFE AF: 0.00383

Gnomad4 OTH AF: 0.00401

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperthyroxinemia, dystransthyretinemic;C2751492:Familial amyloid neuropathy;C5779776:Carpal tunnel syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 27, 2021

- -

Familial amyloid neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.9
Dann	Benign	0.52

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3794885; hg19: chr18-29171123;