5-16473729-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001034850.3(RETREG1):c.*1012G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 152,010 control chromosomes in the GnomAD database, including 10,764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10754 hom., cov: 33)
  • Exomes 𝑓: 0.41 (10 hom.)
• Consequence: RETREG1 NM_001034850.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0560

Genes affected

RETREG1 (HGNC:25964): (reticulophagy regulator 1) The protein encoded by this gene is a cis-Golgi transmembrane protein that may be necessary for the long-term survival of nociceptive and autonomic ganglion neurons. Mutations in this gene are a cause of hereditary sensory and autonomic neuropathy type IIB (HSAN IIB), and this gene may also play a role in susceptibility to vascular dementia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-16473729-C-T is Benign according to our data. Variant chr5-16473729-C-T is described in ClinVar as [Benign]. Clinvar id is 352675.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RETREG1	NM_001034850.3	c.*1012G>A		3_prime_UTR_variant	9/9	ENST00000306320.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RETREG1	ENST00000306320.10	c.*1012G>A		3_prime_UTR_variant	9/9	1	NM_001034850.3

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56486 AN: 151780 Hom.: 10720 Cov.: 33

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.346

GnomAD4 exome AF: 0.409 AC: 45 AN: 110 Hom.: 10 Cov.: 0 AF XY: 0.397 AC XY: 31 AN XY: 78

Gnomad4 FIN exome AF: 0.407

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.373 AC: 56591 AN: 151900 Hom.: 10754 Cov.: 33 AF XY: 0.374 AC XY: 27747 AN XY: 74226

Gnomad4 AFR AF: 0.435

Gnomad4 AMR AF: 0.389

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.460

Gnomad4 SAS AF: 0.399

Gnomad4 FIN AF: 0.393

Gnomad4 NFE AF: 0.325

Gnomad4 OTH AF: 0.353

Alfa AF: 0.337 Hom.: 6497

Bravo AF: 0.375

Asia WGS AF: 0.451 AC: 1566 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.3
Dann	Benign	0.54

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: rs26016; hg19: chr5-16473838;