dbSNP rs28933981: TTR:p.Thr139Met (chr18-31598647-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PM1PP2PP3BP4_StrongBP6BS2_Supporting

The NM_000371.4(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 Benign.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 6 hom. )

Consequence

TTR
NM_000371.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2B:12O:1

Conservation

PhyloP100: 6.09

Publications

57 publications found

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 Gene-Disease associations (from GenCC):

amyloidosis, hereditary systemic 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
familial amyloid neuropathy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary ATTR amyloidosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
heart conduction disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
ATTRV122I amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TTR links:

ENSG00000294516 (HGNC:):

ENSG00000294516 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000371.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000371.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 108 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0149 (below the threshold of 3.09). Trascript score misZ: 1.5458 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary ATTR amyloidosis, heart conduction disease, familial amyloid neuropathy, ATTRV122I amyloidosis, amyloidosis, hereditary systemic 1.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, REVEL, 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 VariationId is 13434.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000371.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	NM_000371.4	MANE Select	c.416C>T	p.Thr139Met	missense	Exon 4 of 4	NP_000362.1	P02766

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTR	ENST00000237014.8	TSL:1 MANE Select	c.416C>T	p.Thr139Met	missense	Exon 4 of 4	ENSP00000237014.4	P02766
TTR	ENST00000649620.1		c.416C>T	p.Thr139Met	missense	Exon 6 of 6	ENSP00000497927.1	P02766
TTR	ENST00000858988.1		c.416C>T	p.Thr139Met	missense	Exon 6 of 6	ENSP00000529047.1

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

GnomAD2 exomes

AF:

0.00151

AC:

379

AN:

251440

AF XY:

0.00155

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 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

African (AFR)

AF:

0.000448

AC:

AN:

33480

American (AMR)

AF:

0.00123

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00349

AC:

3885

AN:

1111998

Other (OTH)

AF:

0.00194

AC:

117

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

248

495

743

990

1238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00171

AC:

261

AN:

152298

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

126

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41562

American (AMR)

AF:

0.00235

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00275

AC:

187

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00230

Hom.:

Bravo

AF:

0.00170

EpiCase

AF:

0.00262

EpiControl

AF:

0.00296

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Amyloidosis, hereditary systemic 1 (3)

not provided (3)

not specified (3)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Charcot-Marie-Tooth disease (1)

Hyperthyroidism (1)

Hyperthyroxinemia, dystransthyretinemic (1)

AMYLOIDOSIS, HEREDITARY SYSTEMIC 1, MODIFIER OF (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.050

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.3

PhyloP100

6.1

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0040

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.87

Mutation Taster

=34/66

disease causing

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over