18-31592902-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000371.4(TTR):c.76G>A(p.Gly26Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0669 in 1,613,656 control chromosomes in the GnomAD database, including 4,228 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G26G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.051 ( 296 hom., cov: 32)

Exomes 𝑓: 0.068 ( 3932 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 1.39

Publications

49 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000371.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 108 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0149 (below the threshold of 3.09). Trascript score misZ: 1.5458 (below the threshold of 3.09). GenCC associations: The gene is linked to familial amyloid neuropathy, amyloidosis, hereditary systemic 1, ATTRV122I amyloidosis, hereditary ATTR amyloidosis, heart conduction disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024395287).

BP6

Variant 18-31592902-G-A is Benign according to our data. Variant chr18-31592902-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0764 is higher than 0.05.

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.76G>A	p.Gly26Ser	missense	Exon 2 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.76G>A	p.Gly26Ser	missense	Exon 2 of 4	ENSP00000237014.4	P02766
TTR	ENST00000649620.1		c.76G>A	p.Gly26Ser	missense	Exon 4 of 6	ENSP00000497927.1	P02766
TTR	ENST00000858988.1		c.76G>A	p.Gly26Ser	missense	Exon 4 of 6	ENSP00000529047.1

Frequencies

GnomAD3 genomes

AF:

0.0514

AC:

7814

AN:

152120

Hom.:

297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0312

Gnomad ASJ

AF:

0.0594

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0782

Gnomad OTH

AF:

0.0435

GnomAD2 exomes

AF:

0.0505

AC:

12700

AN:

251440

AF XY:

0.0503

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0548

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0954

Gnomad NFE exome

AF:

0.0731

Gnomad OTH exome

AF:

0.0535

GnomAD4 exome

AF:

0.0685

AC:

100104

AN:

1461418

Hom.:

3932

Cov.:

AF XY:

0.0668

AC XY:

48569

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.00998

AC:

334

AN:

33474

American (AMR)

AF:

0.0264

AC:

1181

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0577

AC:

1507

AN:

26120

East Asian (EAS)

AF:

0.000176

AC:

AN:

39676

South Asian (SAS)

AF:

0.0139

AC:

1201

AN:

86216

European-Finnish (FIN)

AF:

0.0961

AC:

5127

AN:

53374

Middle Eastern (MID)

AF:

0.00763

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0784

AC:

87122

AN:

1111716

Other (OTH)

AF:

0.0593

AC:

3581

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

5023

10046

15068

20091

25114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3174

6348

9522

12696

15870

<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:

0.0513

AC:

7810

AN:

152238

Hom.:

296

Cov.:

AF XY:

0.0516

AC XY:

3843

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0136

AC:

565

AN:

41544

American (AMR)

AF:

0.0312

AC:

477

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0594

AC:

206

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0133

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.101

AC:

1074

AN:

10590

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0782

AC:

5316

AN:

68010

Other (OTH)

AF:

0.0430

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

363

726

1090

1453

1816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.0640

Hom.:

1377

Bravo

AF:

0.0446

TwinsUK

AF:

0.0672

AC:

249

ALSPAC

AF:

0.0719

AC:

277

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.0780

AC:

671

ExAC

AF:

0.0495

AC:

6014

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0680

EpiControl

AF:

0.0699

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (3)

Amyloidosis, hereditary systemic 1 (2)

Cardiovascular phenotype (1)

Charcot-Marie-Tooth disease (1)

Hyperthyroxinemia, dystransthyretinemic;C2751492:Amyloidosis, hereditary systemic 1;C5779776:Carpal tunnel syndrome 1 (1)

Hypertrophic cardiomyopathy (1)

TTR POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.31

CADD

Benign

9.1

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.15

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.6

PhyloP100

1.4

PrimateAI

Benign

0.29

PROVEAN

Benign

0.11

REVEL

Benign

0.17

Sift

Benign

1.0

Sift4G

Benign

0.78

Polyphen

0.0

Vest4

0.11

MPC

0.46

ClinPred

0.0016

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.077

gMVP

0.68

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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