18-31594143-CAA-CAAA

Variant names:

• chr18-31594143-C-CA
• rs58272364
• NM_000371.4:c.201-966dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000371.4(TTR):​c.201-966dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00723 in 119,044 control chromosomes in the GnomAD database, including 13 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0072 (13 hom., cov: 32)
• Consequence: TTR NM_000371.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.870
• Publications: 1 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00723 (861/119044) while in subpopulation EAS AF = 0.0482 (209/4334). AF 95% confidence interval is 0.0429. There are 13 homozygotes in GnomAd4. There are 449 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 861 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000371.4. 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
	TTR	NM_000371.4	MANE Select	c.201-966dupA		intron	N/A	NP_000362.1	P02766

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	ENST00000237014.8	TSL:1 MANE Select	c.201-977_201-976insA		intron	N/A	ENSP00000237014.4	P02766
	TTR	ENST00000649620.1		c.201-977_201-976insA		intron	N/A	ENSP00000497927.1	P02766
	TTR	ENST00000858988.1		c.201-977_201-976insA		intron	N/A	ENSP00000529047.1

Frequencies

GnomAD3 genomes AF: 0.00717 AC: 853 AN: 119002 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0481

Gnomad SAS AF: 0.0252

Gnomad FIN AF: 0.00163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000929

Gnomad OTH AF: 0.00557

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

GnomAD4 genome AF: 0.00723 AC: 861 AN: 119044 Hom.: 13 Cov.: 32 AF XY: 0.00781 AC XY: 449 AN XY: 57468

African (AFR) AF: 0.0137 AC: 436 AN: 31820

American (AMR) AF: 0.00385 AC: 46 AN: 11938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2924

East Asian (EAS) AF: 0.0482 AC: 209 AN: 4334

South Asian (SAS) AF: 0.0250 AC: 96 AN: 3836

European-Finnish (FIN) AF: 0.00163 AC: 11 AN: 6730

Middle Eastern (MID) AF: 0.00417 AC: 1 AN: 240

European-Non Finnish (NFE) AF: 0.000929 AC: 51 AN: 54910

Other (OTH) AF: 0.00674 AC: 11 AN: 1632

Alfa AF: 0.000164 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs58272364; hg19: chr18-29174106;