rs1800458

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Transthyretin (size 126) in uniprot entity TTHY_HUMAN there are 141 pathogenic changes around while only 6 benign (96%) in NM_000371.4

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 [Likely_benign]. Clinvar id is 13452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31592902-G-A is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4 link	c.76G>A	p.Gly26Ser	missense_variant	Exon 2 of 4	ENST00000237014.8	NP_000362.1	P02766E9KL36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8 link	c.76G>A	p.Gly26Ser	missense_variant	Exon 2 of 4	1	NM_000371.4	ENSP00000237014.4		P02766

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

GnomAD3 exomes

AF:

0.0505

AC:

12700

AN:

251440

Hom.:

468

AF XY:

0.0503

AC XY:

6830

AN XY:

135892

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 SAS exome

AF:

0.0132

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

Gnomad4 AFR exome

AF:

0.00998

Gnomad4 AMR exome

AF:

0.0264

Gnomad4 ASJ exome

AF:

0.0577

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0139

Gnomad4 FIN exome

AF:

0.0961

Gnomad4 NFE exome

AF:

0.0784

Gnomad4 OTH exome

AF:

0.0593

GnomAD4 genome

AF:

0.0513

AC:

7810

AN:

152238

Hom.:

296

Cov.:

AF XY:

0.0516

AC XY:

3843

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0136

Gnomad4 AMR

AF:

0.0312

Gnomad4 ASJ

AF:

0.0594

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0133

Gnomad4 FIN

AF:

0.101

Gnomad4 NFE

AF:

0.0782

Gnomad4 OTH

AF:

0.0430

Alfa

AF:

0.0674

Hom.:

972

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

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

May 08, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 17, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly26Ser variant in TTR is classified as benign because it has been identified in 10.1% (1074/10590) of Finnish European chromosomes, including 53 homozygotes and 5.1% (7814/152120) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), including 297 homozygotes. ACMG/AMP Criteria applied: BA1. -

Jun 20, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Dec 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28911993, 26959691, 7868124, 29520877, 2040864) -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Amyloidosis, hereditary systemic 1

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Jul 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TRANSTHYRETIN POLYMORPHISM

Benign:1

Jul 01, 1990

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hypertrophic cardiomyopathy

Benign:1

Sep 29, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 21, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.31

CADD

Benign

9.1

DANN

Benign

0.33

DEOGEN2

Benign

0.15

T;T;T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.74

.;T;T;T

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.6

L;L;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

0.11

.;N;.;.

REVEL

Benign

0.17

Sift

Benign

1.0

.;T;.;.

Sift4G

Benign

0.78

.;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.11, 0.11, 0.084

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over