rs1667250

Positions:

• chr18-31597193-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000371.4(TTR):​c.337-1375C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 152,078 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (263 hom., cov: 32)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: TTR NM_000371.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.980

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]

LOC124904277 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTR	NM_000371.4	c.337-1375C>T		intron_variant		ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-1498G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.337-1375C>T		intron_variant		1	NM_000371.4	ENSP00000237014	P1
TTR	ENST00000610404.5	c.241-1375C>T		intron_variant		5		ENSP00000477599
TTR	ENST00000649620.1	c.337-1375C>T		intron_variant				ENSP00000497927	P1

Frequencies

GnomAD3 genomes AF: 0.0362 AC: 5492 AN: 151864 Hom.: 259 Cov.: 32

Gnomad AFR AF: 0.0921

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0583

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0267

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.0258

GnomAD4 exome AF: 0.0208 AC: 2 AN: 96 Hom.: 0 Cov.: 0 AF XY: 0.0278 AC XY: 2 AN XY: 72

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0364 AC: 5527 AN: 151982 Hom.: 263 Cov.: 32 AF XY: 0.0373 AC XY: 2769 AN XY: 74282

Gnomad4 AFR AF: 0.0925

Gnomad4 AMR AF: 0.0584

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0265

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0195 Hom.: 17

Bravo AF: 0.0415

Asia WGS AF: 0.115 AC: 403 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.1
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1667250; hg19: chr18-29177156;