18-31598550-G-C

Position:

chr18-31598550-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000237014.8(TTR):c.337-18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.045 in 1,612,924 control chromosomes in the GnomAD database, including 2,162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 370 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1792 hom. )

Consequence

TTR
ENST00000237014.8 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.503

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 18-31598550-G-C is Benign according to our data. Variant chr18-31598550-G-C is described in ClinVar as [Benign]. Clinvar id is 36892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31598550-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4 linkuse as main transcript	c.337-18G>C		intron_variant		ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1 linkuse as main transcript	n.129-2855C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris
TTR	ENST00000237014.8 linkuse as main transcript	c.337-18G>C	intron_variant	1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000610404.5 linkuse as main transcript	c.241-18G>C	intron_variant	5		ENSP00000477599
TTR	ENST00000649620.1 linkuse as main transcript	c.337-18G>C	intron_variant			ENSP00000497927	P1

Frequencies

GnomAD3 genomes

AF:

0.0604

AC:

9168

AN:

151788

Hom.:

367

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0952

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.0499

Gnomad EAS

AF:

0.0720

Gnomad SAS

AF:

0.0222

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0389

Gnomad OTH

AF:

0.0581

GnomAD3 exomes

AF:

0.0572

AC:

14357

AN:

250802

Hom.:

696

AF XY:

0.0507

AC XY:

6878

AN XY:

135612

show subpopulations

Gnomad AFR exome

AF:

0.0969

Gnomad AMR exome

AF:

0.155

Gnomad ASJ exome

AF:

0.0551

Gnomad EAS exome

AF:

0.0740

Gnomad SAS exome

AF:

0.0212

Gnomad FIN exome

AF:

0.0194

Gnomad NFE exome

AF:

0.0366

Gnomad OTH exome

AF:

0.0477

GnomAD4 exome

AF:

0.0434

AC:

63455

AN:

1461026

Hom.:

1792

Cov.:

AF XY:

0.0421

AC XY:

30588

AN XY:

726838

show subpopulations

Gnomad4 AFR exome

AF:

0.0984

Gnomad4 AMR exome

AF:

0.149

Gnomad4 ASJ exome

AF:

0.0525

Gnomad4 EAS exome

AF:

0.0608

Gnomad4 SAS exome

AF:

0.0198

Gnomad4 FIN exome

AF:

0.0196

Gnomad4 NFE exome

AF:

0.0396

Gnomad4 OTH exome

AF:

0.0451

GnomAD4 genome

AF:

0.0604

AC:

9175

AN:

151898

Hom.:

370

Cov.:

AF XY:

0.0590

AC XY:

4384

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0949

Gnomad4 AMR

AF:

0.104

Gnomad4 ASJ

AF:

0.0499

Gnomad4 EAS

AF:

0.0722

Gnomad4 SAS

AF:

0.0222

Gnomad4 FIN

AF:

0.0171

Gnomad4 NFE

AF:

0.0389

Gnomad4 OTH

AF:

0.0575

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0706

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 23, 2022	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 29, 2022	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2017

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. -

Amyloidosis, hereditary systemic 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.29

DANN

Benign

0.59

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