Genetic Variant TTR:c.201-966dupA (chr18-31594143-C-CA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.870

Publications

1 publications found

Variant links:

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

TTR links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4 link	c.201-966dupA		intron_variant	Intron 2 of 3	ENST00000237014.8	NP_000362.1	P02766E9KL36

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTR	ENST00000237014.8 link	c.201-977_201-976insA	intron_variant	Intron 2 of 3	1	NM_000371.4	ENSP00000237014.4	P02766
TTR	ENST00000649620.1 link	c.201-977_201-976insA	intron_variant	Intron 4 of 5			ENSP00000497927.1	P02766
TTR	ENST00000610404.5 link	c.105-977_105-976insA	intron_variant	Intron 2 of 3	5		ENSP00000477599.2	A0A087WT59
TTR	ENST00000541025.2 link	n.227-977_227-976insA	intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00717

AC:

853

AN:

119002

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00781

AC XY:

449

AN XY:

57468

show subpopulations

African (AFR)

AF:

0.0137

AC:

436

AN:

31820

American (AMR)

AF:

0.00385

AC:

AN:

11938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2924

East Asian (EAS)

AF:

0.0482

AC:

209

AN:

4334

South Asian (SAS)

AF:

0.0250

AC:

AN:

3836

European-Finnish (FIN)

AF:

0.00163

AC:

AN:

6730

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000929

AC:

AN:

54910

Other (OTH)

AF:

0.00674

AC:

AN:

1632

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000164

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.87

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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18-31594143-CAA-CAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over