chr5-16474535-T-G

Position:

• chr5-16474535-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001034850.3(RETREG1):​c.*206A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 617,616 control chromosomes in the GnomAD database, including 33,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7000 hom., cov: 33)
  • Exomes 𝑓: 0.33 (26025 hom.)
• Consequence: RETREG1 NM_001034850.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.66

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 5-16474535-T-G is Benign according to our data. Variant chr5-16474535-T-G is described in ClinVar as [Benign]. Clinvar id is 352681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RETREG1	NM_001034850.3	c.*206A>C		3_prime_UTR_variant	9/9	ENST00000306320.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RETREG1	ENST00000306320.10	c.*206A>C		3_prime_UTR_variant	9/9	1	NM_001034850.3

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44630 AN: 151922 Hom.: 6983 Cov.: 33

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.328 AC: 152582 AN: 465576 Hom.: 26025 Cov.: 6 AF XY: 0.330 AC XY: 81446 AN XY: 246620

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.397

Gnomad4 ASJ exome AF: 0.284

Gnomad4 EAS exome AF: 0.475

Gnomad4 SAS exome AF: 0.394

Gnomad4 FIN exome AF: 0.363

Gnomad4 NFE exome AF: 0.305

Gnomad4 OTH exome AF: 0.316

GnomAD4 genome AF: 0.294 AC: 44687 AN: 152040 Hom.: 7000 Cov.: 33 AF XY: 0.298 AC XY: 22132 AN XY: 74314

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.295

Gnomad4 EAS AF: 0.467

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.288

Alfa AF: 0.289 Hom.: 6540

Bravo AF: 0.288

Asia WGS AF: 0.432 AC: 1500 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.41
CADD	Benign	9.9
DANN	Benign	0.85

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: rs32147; hg19: chr5-16474644;