chr18-31592966-A-G

Position:

chr18-31592966-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS2_Supporting

The NM_000371.4(TTR):c.140A>G(p.Asn47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 2.00

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 Likely_benign. Variant got -1 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=0.21249506).

BS2

High AC in GnomAd4 at 9 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.140A>G	p.Asn47Ser	missense_variant	2/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8 linkuse as main transcript	c.140A>G	p.Asn47Ser	missense_variant	2/4	1	NM_000371.4	ENSP00000237014	P1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251466

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 17, 2014	The Asn47Ser variant in TTR has been not been previously reported in any other f amilies with cardiomyopathy, but has been identified in 2/4406 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs145551875). Asparagine (Asn) at position 47 is not conserved in ev olution with one primate (bushbaby) carrying a serine (Ser; this variant) at thi s position. This raises the possibility that this change may be tolerated. Addit ional computational analyses (biochemical amino acid properties, AlignGVGD, Poly Phen2, and SIFT) also suggest that the Asn47Ser variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. Although these data supports that this variant may be benign, additional studies are needed to fully assess its clinical significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 21, 2018	The TTR c.140A>G; p.Asn47Ser variant (rs145551875), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 178279). This variant is found on five chromosomes in the African population in the Genome Aggregation Database. The asparagine at codon 47 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Asn47Ser variant is uncertain at this time. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2015	This variant is denoted p.Asn47Ser (AAT>AGT): c.140 A>G in exon 2 of the TTR gene (NM_000371.3). The N47S variant in the TTR gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. N47S was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations in nearby residues (A45T, V48M) have been reported in association with TTR-related amyloidosis, supporting the functional importance of this region of the protein. However, N47S is only a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. In addition, the N47 residue is not well conserved across species, and in silico analysis predicts N47S is benign to the protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if N47S is a disease-causing mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 12, 2020	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2022

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2021

The p.N47S variant (also known as c.140A>G), located in coding exon 2 of the TTR gene, results from an A to G substitution at nucleotide position 140. The asparagine at codon 47 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Amyloidosis, hereditary systemic 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 47 of the TTR protein (p.Asn47Ser). This variant is present in population databases (rs145551875, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32746448). ClinVar contains an entry for this variant (Variation ID: 178279). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.29

CADD

Benign

6.8

DANN

Benign

0.57

DEOGEN2

Pathogenic

0.83

D;D;T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.79

.;T;T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Uncertain

-0.061

MutationAssessor

Benign

1.8

L;L;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.1

.;N;.;.

REVEL

Uncertain

0.30

Sift

Benign

0.16

.;T;.;.

Sift4G

Benign

0.62

.;T;T;T

Polyphen

0.0010

B;B;.;.

Vest4

0.24, 0.27, 0.36

MVP

0.90

MPC

0.37

ClinPred

0.036

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.79

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