18-31596910-G-C

Variant names:

• chr18-31596910-G-C
• rs7235277
• NM_000371.4:c.336+1655G>C

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+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
• Publications: 3 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=-0.85).
• 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 rank	MANE	Protein	UniProt
TTR	NM_000371.4	c.336+1655G>C		intron_variant	Intron 3 of 3	ENST00000237014.8	NP_000362.1
LOC124904277	XR_007066326.1	n.129-1215C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTR	ENST00000237014.8	c.336+1655G>C		intron_variant	Intron 3 of 3	1	NM_000371.4	ENSP00000237014.4
TTR	ENST00000649620.1	c.336+1655G>C		intron_variant	Intron 5 of 5			ENSP00000497927.1
TTR	ENST00000610404.5	c.240+1655G>C		intron_variant	Intron 3 of 3	5		ENSP00000477599.2
ENSG00000294516	ENST00000724044.1	n.286-1215C>G		intron_variant	Intron 2 of 2

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

African (AFR) AF: 0.330 AC: 13678 AN: 41470

American (AMR) AF: 0.291 AC: 4445 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1362 AN: 3470

East Asian (EAS) AF: 0.297 AC: 1533 AN: 5160

South Asian (SAS) AF: 0.271 AC: 1305 AN: 4810

European-Finnish (FIN) AF: 0.255 AC: 2702 AN: 10588

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.342 AC: 23234 AN: 67950

Other (OTH) AF: 0.359 AC: 756 AN: 2106

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
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7235277; hg19: chr18-29176873;