rs121918092

Variant names:

• chr18-31598617-C-T
• rs121918092
• NM_000371.4:c.386C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM5 PP2 BS2_Supporting

The NM_000371.4(TTR):​c.386C>T​(p.Ala129Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A129S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 2.42
• Publications: 5 publications found

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

ENSG00000294516 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000371.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31598616-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 626843.
• 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.
• BS2: High AC in GnomAd4 at 5 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.386C>T	p.Ala129Val	missense	Exon 4 of 4	NP_000362.1	P02766

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	ENST00000237014.8	TSL:1 MANE Select	c.386C>T	p.Ala129Val	missense	Exon 4 of 4	ENSP00000237014.4	P02766
	TTR	ENST00000649620.1		c.386C>T	p.Ala129Val	missense	Exon 6 of 6	ENSP00000497927.1	P02766
	TTR	ENST00000858988.1		c.386C>T	p.Ala129Val	missense	Exon 6 of 6	ENSP00000529047.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251442 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000467 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Amyloidosis, hereditary systemic 1 (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Charcot-Marie-Tooth disease (1)
-	-	-	Hyperthyroxinemia, dystransthyretinemic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.49	N
PhyloP100		2.4
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.57	N
REVEL	Uncertain	0.50
Sift	Benign	0.53	T
Sift4G	Benign	0.98	T
Polyphen		0.41	B
Vest4		0.48
MutPred		0.66		Loss of glycosylation at T126 (P = 0.2601)
MVP		0.98
MPC		0.53
ClinPred		0.10	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.90
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs121918092; hg19: chr18-29178580;