rs3764476

Variant names:

• chr18-31596497-C-A
• rs3764476
• NM_000371.4:c.336+1242C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-31596497-C-A
• chr18-31596497-C-G
• chr18-31596497-C-T

Variant summary

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

The NM_000371.4(TTR):​c.336+1242C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 151,780 control chromosomes in the GnomAD database, including 8,500 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 0.33 (8500 hom., cov: 31)
• Consequence: TTR NM_000371.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• Publications: 6 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=-0.76).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.336+1242C>A		intron_variant	Intron 3 of 3	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-802G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.336+1242C>A		intron_variant	Intron 3 of 3	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.336+1242C>A		intron_variant	Intron 5 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.240+1242C>A		intron_variant	Intron 3 of 3	5		ENSP00000477599.2
ENSG00000294516	ENST00000724044.1	n.286-802G>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50262 AN: 151662 Hom.: 8486 Cov.: 31

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.358

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

GnomAD4 genome AF: 0.332 AC: 50317 AN: 151780 Hom.: 8500 Cov.: 31 AF XY: 0.327 AC XY: 24270 AN XY: 74176

African (AFR) AF: 0.353 AC: 14593 AN: 41328

American (AMR) AF: 0.294 AC: 4488 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1360 AN: 3464

East Asian (EAS) AF: 0.297 AC: 1531 AN: 5158

South Asian (SAS) AF: 0.257 AC: 1234 AN: 4800

European-Finnish (FIN) AF: 0.255 AC: 2694 AN: 10546

Middle Eastern (MID) AF: 0.507 AC: 148 AN: 292

European-Non Finnish (NFE) AF: 0.342 AC: 23205 AN: 67922

Other (OTH) AF: 0.360 AC: 756 AN: 2098

Alfa AF: 0.337 Hom.: 11310

Bravo AF: 0.337

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.6
DANN	Benign	0.84
PhyloP100		2.1
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: rs3764476; hg19: chr18-29176460;