18-31596673-TAAA-TAAAA

Variant names:

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

Variant summary

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

The NM_000371.4(TTR):​c.336+1432dupA 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 0.019 (72 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 (AFR) allele frequency at 95% confidence interval = 0.0588 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+1432dupA		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+1418_336+1419insA		intron	N/A	ENSP00000237014.4
	TTR	ENST00000649620.1		c.336+1418_336+1419insA		intron	N/A	ENSP00000497927.1
	TTR	ENST00000610404.5	TSL:5	c.240+1418_240+1419insA		intron	N/A	ENSP00000477599.2

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2743 AN: 144816 Hom.: 73 Cov.: 0

Gnomad AFR AF: 0.0608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00763

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00122

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.00131

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.00174

Gnomad OTH AF: 0.0166

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

GnomAD4 genome AF: 0.0190 AC: 2747 AN: 144880 Hom.: 72 Cov.: 0 AF XY: 0.0184 AC XY: 1290 AN XY: 70290

African (AFR) AF: 0.0608 AC: 2399 AN: 39456

American (AMR) AF: 0.00755 AC: 109 AN: 14434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00122 AC: 6 AN: 4912

South Asian (SAS) AF: 0.0156 AC: 69 AN: 4434

European-Finnish (FIN) AF: 0.00131 AC: 12 AN: 9148

Middle Eastern (MID) AF: 0.0109 AC: 3 AN: 274

European-Non Finnish (NFE) AF: 0.00174 AC: 115 AN: 65924

Other (OTH) AF: 0.0169 AC: 34 AN: 2006

Alfa AF: 0.000121 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

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: rs10707844; hg19: chr18-29176636;