chr18-31598416-T-G

Variant names:

• chr18-31598416-T-G
• rs1667251
• NM_000371.4:c.337-152T>G

Variant summary

Our verdict is Benign. The variant received -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
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000371.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	NM_000371.4	MANE Select	c.337-152T>G		intron	N/A	NP_000362.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTR	ENST00000237014.8	TSL:1 MANE Select	c.337-152T>G		intron	N/A	ENSP00000237014.4
	TTR	ENST00000649620.1		c.337-152T>G		intron	N/A	ENSP00000497927.1
	TTR	ENST00000610404.5	TSL:5	c.241-152T>G		intron	N/A	ENSP00000477599.2

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

African (AFR) AF: 0.195 AC: 3371 AN: 17304

American (AMR) AF: 0.0795 AC: 2756 AN: 34666

Ashkenazi Jewish (ASJ) AF: 0.00171 AC: 35 AN: 20434

East Asian (EAS) AF: 0.0301 AC: 972 AN: 32268

South Asian (SAS) AF: 0.107 AC: 6802 AN: 63662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35592

Middle Eastern (MID) AF: 0.0149 AC: 63 AN: 4220

European-Non Finnish (NFE) AF: 0.00103 AC: 404 AN: 394034

Other (OTH) AF: 0.0284 AC: 946 AN: 33252

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

African (AFR) AF: 0.195 AC: 8109 AN: 41532

American (AMR) AF: 0.0698 AC: 1068 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.0261 AC: 135 AN: 5182

South Asian (SAS) AF: 0.116 AC: 559 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68028

Other (OTH) AF: 0.0498 AC: 105 AN: 2110

Alfa AF: 0.0484 Hom.: 90

Bravo AF: 0.0752

Asia WGS AF: 0.120 AC: 423 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.9
DANN	Benign	0.55
PhyloP100		-0.0020
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: rs1667251; hg19: chr18-29178379;