18-31598416-T-G

Position:

• chr18-31598416-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000371.4(TTR):​c.337-152T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0323 in 787,716 control chromosomes in the GnomAD database, including 1,832 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 0.066 (894 hom., cov: 33)
  • Exomes 𝑓: 0.024 (938 hom.)
• Consequence: TTR NM_000371.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.337-152T>G		intron_variant		ENST00000237014.8
LOC124904277	XR_007066326.1	n.129-2721A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.337-152T>G		intron_variant		1	NM_000371.4	P1
TTR	ENST00000610404.5	c.241-152T>G		intron_variant		5
TTR	ENST00000649620.1	c.337-152T>G		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 10021 AN: 152166 Hom.: 889 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0262

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0479

GnomAD4 exome AF: 0.0242 AC: 15349 AN: 635432 Hom.: 938 AF XY: 0.0268 AC XY: 9075 AN XY: 339090

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.0795

Gnomad4 ASJ exome AF: 0.00171

Gnomad4 EAS exome AF: 0.0301

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.0284

GnomAD4 genome AF: 0.0661 AC: 10068 AN: 152284 Hom.: 894 Cov.: 33 AF XY: 0.0656 AC XY: 4887 AN XY: 74466

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.0698

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0261

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.0498

Alfa AF: 0.0444 Hom.: 78

Bravo AF: 0.0752

Asia WGS AF: 0.120 AC: 423 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.9
DANN	Benign	0.55

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: rs1667251; hg19: chr18-29178379;