rs13381522

Variant names:

• chr18-31589970-C-T
• rs13381522
• ENST00000649620.1:c.-1-1932C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000649620.1(TTR):​c.-1-1932C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,222 control chromosomes in the GnomAD database, including 2,161 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 0.12 (2161 hom., cov: 33)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.244
• Publications: 2 publications found

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]

TTR Gene-Disease associations (from GenCC):

• amyloidosis, hereditary systemic 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• familial amyloid neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary ATTR amyloidosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• heart conduction disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• ATTRV122I amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

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.-1-1932C>T		intron_variant	Intron 2 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.-27-2926C>T		intron_variant	Intron 1 of 3	5		ENSP00000477599.2
TTR	ENST00000613781.2	c.-1-1932C>T		intron_variant	Intron 1 of 1	5		ENSP00000479174.2
TTR	ENST00000676075.1	c.-1-1932C>T		intron_variant	Intron 1 of 1			ENSP00000502027.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18558 AN: 152104 Hom.: 2149 Cov.: 33

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0498

Gnomad EAS AF: 0.0748

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0255

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0400

Gnomad OTH AF: 0.0975

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

GnomAD4 genome AF: 0.122 AC: 18614 AN: 152222 Hom.: 2161 Cov.: 33 AF XY: 0.121 AC XY: 8982 AN XY: 74430

African (AFR) AF: 0.304 AC: 12629 AN: 41480

American (AMR) AF: 0.129 AC: 1971 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 173 AN: 3472

East Asian (EAS) AF: 0.0750 AC: 389 AN: 5186

South Asian (SAS) AF: 0.0390 AC: 188 AN: 4826

European-Finnish (FIN) AF: 0.0255 AC: 271 AN: 10612

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0400 AC: 2721 AN: 68018

Other (OTH) AF: 0.0965 AC: 204 AN: 2114

Alfa AF: 0.127 Hom.: 370

Bravo AF: 0.140

Asia WGS AF: 0.0700 AC: 244 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.3
DANN	Benign	0.57
PhyloP100		-0.24

Splicing

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

Other links and lift over

dbSNP: rs13381522; hg19: chr18-29169933;