rs3764476

chr18-31596497-C-Achr18-31596497-C-Gchr18-31596497-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. Variant has been reported in Lovd as Benign (no stars).

• 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

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]

LOC124904277 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 18-31596497-C-A is Benign according to our data. Variant chr18-31596497-C-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
TTR	NM_000371.4	c.336+1242C>A		intron_variant		ENST00000237014.8
LOC124904277	XR_007066326.1	n.129-802G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.336+1242C>A		intron_variant		1	NM_000371.4	P1
TTR	ENST00000610404.5	c.240+1242C>A		intron_variant		5
TTR	ENST00000649620.1	c.336+1242C>A		intron_variant				P1

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

Gnomad4 AFR AF: 0.353

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.257

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.360

Alfa AF: 0.336 Hom.: 8507

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3764476; hg19: chr18-29176460;