rs1616887

Variant names:

• chr18-31580789-A-G
• rs1616887
• ENST00000649620.1:c.-101-5013A>G

Variant summary

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

The ENST00000649620.1(TTR):​c.-101-5013A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 152,004 control chromosomes in the GnomAD database, including 24,412 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 0.54 (24412 hom., cov: 31)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 3 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 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.-101-5013A>G		intron_variant	Intron 1 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.-27-12107A>G		intron_variant	Intron 1 of 3	5		ENSP00000477599.2
TTR	ENST00000613781.2	c.-2+4621A>G		intron_variant	Intron 1 of 1	5		ENSP00000479174.2
TTR	ENST00000676075.1	c.-2+4518A>G		intron_variant	Intron 1 of 1			ENSP00000502027.1

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81305 AN: 151886 Hom.: 24340 Cov.: 31

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.528

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

GnomAD4 genome AF: 0.536 AC: 81443 AN: 152004 Hom.: 24412 Cov.: 31 AF XY: 0.530 AC XY: 39352 AN XY: 74304

African (AFR) AF: 0.827 AC: 34304 AN: 41484

American (AMR) AF: 0.513 AC: 7828 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3470

East Asian (EAS) AF: 0.447 AC: 2300 AN: 5142

South Asian (SAS) AF: 0.439 AC: 2115 AN: 4820

European-Finnish (FIN) AF: 0.324 AC: 3422 AN: 10570

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28204 AN: 67928

Other (OTH) AF: 0.531 AC: 1123 AN: 2114

Alfa AF: 0.444 Hom.: 8330

Bravo AF: 0.564

Asia WGS AF: 0.482 AC: 1682 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.14
DANN	Benign	0.61
PhyloP100		-1.4

Splicing

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

Other links and lift over

dbSNP: rs1616887; hg19: chr18-29160752;