chr18-31595189-A-C

Position:

• chr18-31595189-A-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM1 PM2 PP3_Moderate PP5

The NM_000371.4(TTR):​c.270A>C​(p.Lys90Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.107

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 Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_000371.4 (TTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a strand (size 7) in uniprot entity TTHY_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 18-31595189-A-C is Pathogenic according to our data. Variant chr18-31595189-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 13443.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-31595189-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.270A>C	p.Lys90Asn	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.270A>C	p.Lys90Asn	missense_variant	3/4	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.270A>C	p.Lys90Asn	missense_variant	5/6			ENSP00000497927.1
TTR	ENST00000610404.5	c.174A>C	p.Lys58Asn	missense_variant	3/4	5		ENSP00000477599.2
TTR	ENST00000541025.2	n.296A>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;T;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.068
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.9	H;H;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.2	.;D;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	.;D;.;.
Sift4G	Uncertain	0.0090	.;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.45, 0.49, 0.36
MutPred		0.79		Loss of methylation at K90 (P = 0.0029);Loss of methylation at K90 (P = 0.0029);Loss of methylation at K90 (P = 0.0029);Loss of methylation at K90 (P = 0.0029);
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96

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: rs267607160; hg19: chr18-29175152;