rs7235277

chr18-31596910-G-C

Variant summary

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

The NM_000371.4(TTR):c.336+1655G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 152,042 control chromosomes in the GnomAD database, including 8,194 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 (8194 hom., cov: 32)
• Consequence: TTR NM_000371.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.315

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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTR	NM_000371.4	c.336+1655G>C		intron_variant		ENST00000237014.8
LOC124904277	XR_007066326.1	n.129-1215C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTR	ENST00000237014.8	c.336+1655G>C		intron_variant		1	NM_000371.4	P1
TTR	ENST00000610404.5	c.240+1655G>C		intron_variant		5
TTR	ENST00000649620.1	c.336+1655G>C		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49425 AN: 151926 Hom.: 8184 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.357

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

GnomAD4 genome AF: 0.325 AC: 49472 AN: 152042 Hom.: 8194 Cov.: 32 AF XY: 0.321 AC XY: 23855 AN XY: 74296

Gnomad4 AFR AF: 0.330

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.359

Alfa AF: 0.327 Hom.: 1027

Bravo AF: 0.328

Asia WGS AF: 0.265 AC: 923 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	8.3
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7235277; hg19: chr18-29176873;