NM_000371.4:c.199G>A

Variant names:

• chr18-31593025-G-A
• rs387906523
• NM_000371.4:c.199G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000371.4(TTR):​c.199G>A​(p.Gly67Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G67A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTR NM_000371.4 missense, splice_region
• Scores: Splicing: ADA: 0.9697
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.86

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.

• PM1: In a strand (size 7) in uniprot entity TTHY_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_000371.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31593026-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 18-31593025-G-A is Pathogenic according to our data. Variant chr18-31593025-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13459.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-31593025-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.199G>A	p.Gly67Arg	missense_variant, splice_region_variant	Exon 2 of 4	ENST00000237014.8	NP_000362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.199G>A	p.Gly67Arg	missense_variant, splice_region_variant	Exon 2 of 4	1	NM_000371.4	ENSP00000237014.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amyloidosis, hereditary systemic 1 Pathogenic:1

Apr 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.4	.;D;.;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	.;D;.;.
Sift4G	Benign	0.082	.;T;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.73, 0.81, 0.94
MutPred		0.86		Gain of phosphorylation at S70 (P = 0.0992);Gain of phosphorylation at S70 (P = 0.0992);Gain of phosphorylation at S70 (P = 0.0992);Gain of phosphorylation at S70 (P = 0.0992);
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.64
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: rs387906523; hg19: chr18-29172988;