18-31591160-A-T

Variant names:

• chr18-31591160-A-T
• rs3794885
• ENST00000649620.1:c.-1-742A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

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
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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 -13 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 Benign/Likely_benign. ClinVar VariationId is 744399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 630 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649620.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	ENST00000649620.1		c.-1-742A>T		intron	N/A	ENSP00000497927.1	P02766
	TTR	ENST00000858988.1		c.-1-742A>T		intron	N/A	ENSP00000529047.1
	TTR	ENST00000858989.1		c.-1-742A>T		intron	N/A	ENSP00000529048.1

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

African (AFR) AF: 0.00128 AC: 50 AN: 39134

American (AMR) AF: 0.00738 AC: 108 AN: 14630

Ashkenazi Jewish (ASJ) AF: 0.000582 AC: 2 AN: 3434

East Asian (EAS) AF: 0.0178 AC: 89 AN: 4994

South Asian (SAS) AF: 0.0171 AC: 80 AN: 4672

European-Finnish (FIN) AF: 0.00328 AC: 30 AN: 9156

Middle Eastern (MID) AF: 0.00730 AC: 2 AN: 274

European-Non Finnish (NFE) AF: 0.00383 AC: 256 AN: 66772

Other (OTH) AF: 0.00401 AC: 8 AN: 1994

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Amyloidosis, hereditary systemic 1 (1)
-	-	1	Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.52
PhyloP100		0.074

Splicing

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

Other links and lift over

dbSNP: rs3794885; hg19: chr18-29171123;