chr18-31597193-C-T

Variant names:

• chr18-31597193-C-T
• rs1667250
• NM_000371.4:c.337-1375C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.337-1375C>T		intron_variant	Intron 3 of 3	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-1498G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.337-1375C>T		intron_variant	Intron 3 of 3	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.337-1375C>T		intron_variant	Intron 5 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.241-1375C>T		intron_variant	Intron 3 of 3	5		ENSP00000477599.2
ENSG00000294516	ENST00000724044.1	n.286-1498G>A		intron_variant	Intron 2 of 2

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0128 AC: 1 AN: 78

Other (OTH) AF: 0.00 AC: 0 AN: 10

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

African (AFR) AF: 0.0925 AC: 3830 AN: 41418

American (AMR) AF: 0.0584 AC: 891 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0265 AC: 137 AN: 5166

South Asian (SAS) AF: 0.115 AC: 549 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 67982

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

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
PhyloP100		-0.98
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1667250; hg19: chr18-29177156;