ENST00000649620.1:c.-102+9728A>G

Variant names:

• chr18-31566859-A-G
• rs9304102
• ENST00000649620.1:c.-102+9728A>G

Variant summary

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

The ENST00000649620.1(TTR):​c.-102+9728A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 151,950 control chromosomes in the GnomAD database, including 16,694 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 0.46 (16694 hom., cov: 32)
• Consequence: TTR ENST00000649620.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.969
• Publications: 4 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

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 (EAS) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000649620.1	c.-102+9728A>G		intron_variant	Intron 1 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.-28+9728A>G		intron_variant	Intron 1 of 3	5		ENSP00000477599.2

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70000 AN: 151832 Hom.: 16680 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.461 AC: 70045 AN: 151950 Hom.: 16694 Cov.: 32 AF XY: 0.463 AC XY: 34381 AN XY: 74262

African (AFR) AF: 0.344 AC: 14261 AN: 41436

American (AMR) AF: 0.542 AC: 8284 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1812 AN: 3472

East Asian (EAS) AF: 0.677 AC: 3485 AN: 5150

South Asian (SAS) AF: 0.502 AC: 2420 AN: 4818

European-Finnish (FIN) AF: 0.473 AC: 4989 AN: 10540

Middle Eastern (MID) AF: 0.558 AC: 163 AN: 292

European-Non Finnish (NFE) AF: 0.489 AC: 33227 AN: 67946

Other (OTH) AF: 0.481 AC: 1014 AN: 2110

Alfa AF: 0.488 Hom.: 30985

Bravo AF: 0.465

Asia WGS AF: 0.597 AC: 2076 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	6.0
DANN	Benign	0.73
PhyloP100		0.97

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9304102; hg19: chr18-29146822;