chr18-31597008-T-G

Variant names:

• chr18-31597008-T-G
• rs3794884
• NM_000371.4:c.337-1560T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000371.4(TTR):​c.337-1560T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 152,018 control chromosomes in the GnomAD database, including 8,747 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 0.34 (8745 hom., cov: 31)
  • Exomes 𝑓: 0.45 (2 hom.)
• Consequence: TTR NM_000371.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.258
• Publications: 13 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.337-1560T>G		intron_variant	Intron 3 of 3	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-1313A>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.337-1560T>G		intron_variant	Intron 3 of 3	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.337-1560T>G		intron_variant	Intron 5 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.241-1560T>G		intron_variant	Intron 3 of 3	5		ENSP00000477599.2
ENSG00000294516	ENST00000724044.1	n.286-1313A>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51000 AN: 151878 Hom.: 8732 Cov.: 31

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.364

GnomAD4 exome AF: 0.455 AC: 10 AN: 22 Hom.: 2 AF XY: 0.563 AC XY: 9 AN XY: 16

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.455 AC: 10 AN: 22

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.336 AC: 51055 AN: 151996 Hom.: 8745 Cov.: 31 AF XY: 0.332 AC XY: 24630 AN XY: 74298

African (AFR) AF: 0.365 AC: 15136 AN: 41452

American (AMR) AF: 0.295 AC: 4513 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1361 AN: 3466

East Asian (EAS) AF: 0.298 AC: 1541 AN: 5170

South Asian (SAS) AF: 0.273 AC: 1314 AN: 4808

European-Finnish (FIN) AF: 0.255 AC: 2698 AN: 10564

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23265 AN: 67954

Other (OTH) AF: 0.366 AC: 771 AN: 2104

Alfa AF: 0.346 Hom.: 26818

Bravo AF: 0.341

Asia WGS AF: 0.267 AC: 928 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.2
DANN	Benign	0.59
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3794884; hg19: chr18-29176971;