rs2276382

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6BP7BS1BS2_Supporting

The NM_000371.4(TTR):c.417G>A(p.Thr139Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,100 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 12 hom. )

Consequence

TTR
NM_000371.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: -6.06

Publications

4 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:

ENSG00000294516 (HGNC:):

ENSG00000294516 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 18-31598648-G-A is Benign according to our data. Variant chr18-31598648-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43455.

BP7

Synonymous conserved (PhyloP=-6.06 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00101 (1471/1461860) while in subpopulation EAS AF = 0.0182 (724/39700). AF 95% confidence interval is 0.0171. There are 12 homozygotes in GnomAdExome4. There are 713 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 190 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: 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.417G>A	p.Thr139Thr	synonymous	Exon 4 of 4	NP_000362.1	P02766

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTR	ENST00000237014.8	TSL:1 MANE Select	c.417G>A	p.Thr139Thr	synonymous	Exon 4 of 4	ENSP00000237014.4	P02766
TTR	ENST00000649620.1		c.417G>A	p.Thr139Thr	synonymous	Exon 6 of 6	ENSP00000497927.1	P02766
TTR	ENST00000858988.1		c.417G>A	p.Thr139Thr	synonymous	Exon 6 of 6	ENSP00000529047.1

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

190

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0166

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00342

AC:

861

AN:

251416

AF XY:

0.00304

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0207

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00101

AC:

1471

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

713

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.0102

AC:

454

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0182

AC:

724

AN:

39700

South Asian (SAS)

AF:

0.00167

AC:

144

AN:

86258

European-Finnish (FIN)

AF:

0.000506

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

1112004

Other (OTH)

AF:

0.000844

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

111

222

332

443

554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00125

AC:

190

AN:

152240

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41548

American (AMR)

AF:

0.00516

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0166

AC:

AN:

5168

South Asian (SAS)

AF:

0.00207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000634

Hom.:

Bravo

AF:

0.00189

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Amyloidosis, hereditary systemic 1 (3)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Charcot-Marie-Tooth disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.30

(source)

DANN

Benign

0.69

PhyloP100

-6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over