18-31596673-TAAA-TA

Variant names:

• chr18-31596673-TAA-T
• rs10707844
• NM_000371.4:c.336+1431_336+1432delAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000237014.8(TTR):​c.336+1419_336+1420delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.031 (134 hom., cov: 0)
• Consequence: TTR ENST00000237014.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.74
• Publications: 1 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0779 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000237014.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	NM_000371.4	MANE Select	c.336+1431_336+1432delAA		intron	N/A	NP_000362.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	ENST00000237014.8	TSL:1 MANE Select	c.336+1419_336+1420delAA		intron	N/A	ENSP00000237014.4
	TTR	ENST00000649620.1		c.336+1419_336+1420delAA		intron	N/A	ENSP00000497927.1
	TTR	ENST00000610404.5	TSL:5	c.240+1419_240+1420delAA		intron	N/A	ENSP00000477599.2

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4452 AN: 144734 Hom.: 133 Cov.: 0

Gnomad AFR AF: 0.0800

Gnomad AMI AF: 0.0125

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00853

Gnomad SAS AF: 0.00427

Gnomad FIN AF: 0.00560

Gnomad MID AF: 0.0236

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0226

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0309 AC: 4468 AN: 144806 Hom.: 134 Cov.: 0 AF XY: 0.0300 AC XY: 2105 AN XY: 70256

African (AFR) AF: 0.0802 AC: 3166 AN: 39466

American (AMR) AF: 0.0242 AC: 350 AN: 14434

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 49 AN: 3408

East Asian (EAS) AF: 0.00855 AC: 42 AN: 4910

South Asian (SAS) AF: 0.00406 AC: 18 AN: 4434

European-Finnish (FIN) AF: 0.00560 AC: 51 AN: 9110

Middle Eastern (MID) AF: 0.0221 AC: 6 AN: 272

European-Non Finnish (NFE) AF: 0.0111 AC: 730 AN: 65880

Other (OTH) AF: 0.0224 AC: 45 AN: 2010

Alfa AF: 0.00254 Hom.: 296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10707844; hg19: chr18-29176636;