rs28933981

Positions:

chr18-31598647-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP3BP4_StrongBP6BS2_Supporting

The ENST00000237014.8(TTR):c.416C>T(p.Thr139Met) variant causes a missense change. The variant allele was found at a frequency of 0.0027 in 1,614,166 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T139T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 6 hom. )

Consequence

TTR
ENST00000237014.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:12O:1

Conservation

PhyloP100: 6.09

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:

LOC124904277 (HGNC:):

LOC124904277 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in ENST00000237014.8

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI, PROVEAN was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.04956785).

BP6

Variant 18-31598647-C-T is Benign according to our data. Variant chr18-31598647-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13434.We mark this variant Likely_benign, oryginal submissions are: {Likely_pathogenic=1, Benign=7, Likely_benign=4}. Variant chr18-31598647-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 261 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4 linkuse as main transcript	c.416C>T	p.Thr139Met	missense_variant	4/4	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1 linkuse as main transcript	n.129-2952G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TTR	ENST00000237014.8 linkuse as main transcript	c.416C>T	p.Thr139Met	missense_variant	4/4	1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000649620.1 linkuse as main transcript	c.416C>T	p.Thr139Met	missense_variant	6/6			ENSP00000497927	P1
TTR	ENST00000610404.5 linkuse as main transcript	c.320C>T	p.Thr107Met	missense_variant	4/4	5		ENSP00000477599

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

261

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00275

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00151

AC:

379

AN:

251440

Hom.:

AF XY:

0.00155

AC XY:

210

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00284

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.00281

AC:

4103

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00274

AC XY:

1990

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.00349

Gnomad4 OTH exome

AF:

0.00194

GnomAD4 genome

AF:

0.00171

AC:

261

AN:

152298

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

126

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00275

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00232

Hom.:

Bravo

AF:

0.00170

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00147

AC:

179

EpiCase

AF:

0.00262

EpiControl

AF:

0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:12Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 15, 2021	The p.Thr139Met variant in TTR is classified as benign because it has been identified in 0.3% (351/129156) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, this variant has been reported in both unaffected individuals as well as in individuals with asymptomatic euthyroid hyperthyroxinemia (Scrimshaw 1992, Alves 1997). Functional and clinical studies indicate that this variant may provide protective benefit against TTR amyloidosis by improving protein stability and reducing the propensity to form amyloidogenic aggregates (Quintas 1997, Almeida 2000, Hammarstrom 2001, Costa 2008, Palhano 2009, Borgault 2011). ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	TTR: BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

Amyloidosis, hereditary systemic 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hyperthyroxinemia, dystransthyretinemic

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Sep 01, 2023

PS3,PS4_Moderate,PP4 -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 21, 2018

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2018

This alteration is classified as likely 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. -

AMYLOIDOSIS, HEREDITARY SYSTEMIC 1, MODIFIER OF

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 28, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;D;T;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.050

T;T;T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.3

M;M;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

.;N;.;.

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0090

.;D;.;.

Sift4G

Uncertain

0.0040

.;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.79, 0.86, 0.73

MVP

0.99

MPC

1.4

ClinPred

0.11

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.87

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