rs62093482

Variant names:

• chr18-31598936-C-T
• rs62093482
• ENST00000724044.1:n.286-3241G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000724044.1(ENSG00000294516):​n.286-3241G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 508,938 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (34 hom., cov: 33)
  • Exomes 𝑓: 0.024 (124 hom.)
• Consequence: ENSG00000294516 ENST00000724044.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.482
• Publications: 8 publications found

Genes affected

ENSG00000294516 (HGNC:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-31598936-C-T is Benign according to our data. Variant chr18-31598936-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 892146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0183 (2785/152192) while in subpopulation NFE AF = 0.0285 (1939/68014). AF 95% confidence interval is 0.0275. There are 34 homozygotes in GnomAd4. There are 1320 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124904277	XR_007066326.1	n.129-3241G>A		intron_variant	Intron 1 of 1
TTR	NM_000371.4	c.*261C>T		downstream_gene_variant		ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000294516	ENST00000724044.1	n.286-3241G>A		intron_variant	Intron 2 of 2
TTR	ENST00000237014.8	c.*261C>T		downstream_gene_variant		1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.*261C>T		downstream_gene_variant				ENSP00000497927.1
TTR	ENST00000610404.5	c.*261C>T		downstream_gene_variant		5		ENSP00000477599.2

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2788 AN: 152074 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00527

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0249

GnomAD4 exome AF: 0.0237 AC: 8455 AN: 356746 Hom.: 124 Cov.: 3 AF XY: 0.0232 AC XY: 4400 AN XY: 189844

African (AFR) AF: 0.00590 AC: 61 AN: 10336

American (AMR) AF: 0.0116 AC: 187 AN: 16096

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 160 AN: 10726

East Asian (EAS) AF: 0.000543 AC: 12 AN: 22100

South Asian (SAS) AF: 0.0212 AC: 912 AN: 43066

European-Finnish (FIN) AF: 0.0221 AC: 431 AN: 19494

Middle Eastern (MID) AF: 0.0115 AC: 17 AN: 1484

European-Non Finnish (NFE) AF: 0.0293 AC: 6231 AN: 212964

Other (OTH) AF: 0.0217 AC: 444 AN: 20480

GnomAD4 genome AF: 0.0183 AC: 2785 AN: 152192 Hom.: 34 Cov.: 33 AF XY: 0.0177 AC XY: 1320 AN XY: 74414

African (AFR) AF: 0.00525 AC: 218 AN: 41526

American (AMR) AF: 0.0150 AC: 229 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4818

European-Finnish (FIN) AF: 0.0197 AC: 208 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0285 AC: 1939 AN: 68014

Other (OTH) AF: 0.0242 AC: 51 AN: 2110

Alfa AF: 0.0249 Hom.: 122

Bravo AF: 0.0169

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Amyloidosis, hereditary systemic 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.7
DANN	Benign	0.75
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs62093482; hg19: chr18-29178899;