rs1804117

Positions:

• chr18-31595217-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000371.4(TTR):​c.298A>G​(p.Lys100Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.22

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a helix (size 6) in uniprot entity TTHY_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.298A>G	p.Lys100Glu	missense_variant	3/4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.298A>G	p.Lys100Glu	missense_variant	3/4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.298A>G	p.Lys100Glu	missense_variant	5/6			ENSP00000497927.1
TTR	ENST00000610404.5	c.202A>G	p.Lys68Glu	missense_variant	3/4	5		ENSP00000477599.2
TTR	ENST00000541025.2	n.324A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.72	D;D;T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	.;T;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.7	L;L;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.2	.;N;.;.
REVEL	Uncertain	0.63
Sift	Benign	0.11	.;T;.;.
Sift4G	Benign	0.49	.;T;T;T
Polyphen		0.098	B;B;.;.
Vest4		0.52, 0.48, 0.43
MutPred		0.63		Loss of methylation at K100 (P = 0.0152);Loss of methylation at K100 (P = 0.0152);Loss of methylation at K100 (P = 0.0152);Loss of methylation at K100 (P = 0.0152);
MVP		0.96
MPC		0.71
ClinPred		0.49	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.94

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: rs1804117; hg19: chr18-29175180;