rs1800458

chr18-31592902-G-Achr18-31592902-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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. 14/19 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.39

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain 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/exons	MANE	UniProt
TTR	NM_000371.4	c.76G>A	p.Gly26Ser	missense_variant	2/4	ENST00000237014.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.76G>A	p.Gly26Ser	missense_variant	2/4	1	NM_000371.4	P1

Frequencies

GnomAD3 genomes AF: 0.0514 AC: 7814 AN: 152120 Hom.: 297 Cov.: 32

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

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.: 31 AF XY: 0.0668 AC XY: 48569 AN XY: 727010

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.: 32 AF XY: 0.0516 AC XY: 3843 AN XY: 74424

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: 75

ESP6500EA AF: 0.0780 AC: 671

ExAC AF: 0.0495 AC: 6014

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0680

EpiControl AF: 0.0699

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 17, 2023	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 20, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2018	This variant is associated with the following publications: (PMID: 28911993, 26959691, 7868124, 29520877, 2040864) -

Familial amyloid neuropathy Benign:2

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). 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Hyperthyroxinemia, dystransthyretinemic;C2751492:Familial amyloid neuropathy;C5779776:Carpal tunnel syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 16, 2021

- -

TRANSTHYRETIN POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 01, 1990

- -

Hypertrophic cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 29, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2015

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	T
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	N
MetaRNN	Benign	0.0024	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L;L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
Polyphen		0.0	B;B;.;.
Vest4		0.11, 0.11, 0.084
MPC		0.46
ClinPred		0.0016	T
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

Other links and lift over

dbSNP: rs1800458; hg19: chr18-29172865;