18-31596673-TAAA-TAA

Variant names:

• chr18-31596673-TA-T
• rs10707844
• NM_000371.4:c.336+1432delA

Variant summary

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

The NM_000371.4(TTR):​c.336+1432delA 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 0.38 (10259 hom., cov: 0)
• Consequence: TTR NM_000371.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.05
• 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 (NFE) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000371.4. 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+1432delA		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+1419delA		intron	N/A	ENSP00000237014.4
	TTR	ENST00000649620.1		c.336+1419delA		intron	N/A	ENSP00000497927.1
	TTR	ENST00000610404.5	TSL:5	c.240+1419delA		intron	N/A	ENSP00000477599.2

Frequencies

GnomAD3 genomes AF: 0.383 AC: 55384 AN: 144532 Hom.: 10258 Cov.: 0

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.523

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.409

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

GnomAD4 genome AF: 0.383 AC: 55411 AN: 144600 Hom.: 10259 Cov.: 0 AF XY: 0.382 AC XY: 26773 AN XY: 70150

African (AFR) AF: 0.338 AC: 13350 AN: 39442

American (AMR) AF: 0.337 AC: 4849 AN: 14386

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1551 AN: 3408

East Asian (EAS) AF: 0.311 AC: 1523 AN: 4904

South Asian (SAS) AF: 0.292 AC: 1296 AN: 4434

European-Finnish (FIN) AF: 0.384 AC: 3474 AN: 9040

Middle Eastern (MID) AF: 0.536 AC: 147 AN: 274

European-Non Finnish (NFE) AF: 0.427 AC: 28094 AN: 65828

Other (OTH) AF: 0.409 AC: 819 AN: 2002

Alfa AF: 0.185 Hom.: 296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;