rs16868675

Positions:

• chr5-16481076-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001034850.3(RETREG1):​c.603T>C​(p.Cys201=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0285 in 1,610,944 control chromosomes in the GnomAD database, including 2,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (1056 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1233 hom.)
• Consequence: RETREG1 NM_001034850.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.08

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-16481076-A-G is Benign according to our data. Variant chr5-16481076-A-G is described in ClinVar as [Benign]. Clinvar id is 137274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-16481076-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RETREG1	NM_001034850.3	c.603T>C	p.Cys201=	synonymous_variant	5/9	ENST00000306320.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RETREG1	ENST00000306320.10	c.603T>C	p.Cys201=	synonymous_variant	5/9	1	NM_001034850.3

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11460 AN: 152040 Hom.: 1044 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00536

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0622

GnomAD3 exomes AF: 0.0284 AC: 7045 AN: 248430 Hom.: 413 AF XY: 0.0247 AC XY: 3332 AN XY: 134764

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.00367

Gnomad SAS exome AF: 0.00484

Gnomad FIN exome AF: 0.00606

Gnomad NFE exome AF: 0.0205

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0236 AC: 34470 AN: 1458786 Hom.: 1233 Cov.: 30 AF XY: 0.0224 AC XY: 16224 AN XY: 725836

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.0121

Gnomad4 EAS exome AF: 0.00462

Gnomad4 SAS exome AF: 0.00501

Gnomad4 FIN exome AF: 0.00709

Gnomad4 NFE exome AF: 0.0204

Gnomad4 OTH exome AF: 0.0307

GnomAD4 genome AF: 0.0757 AC: 11514 AN: 152158 Hom.: 1056 Cov.: 32 AF XY: 0.0730 AC XY: 5435 AN XY: 74412

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.0331

Gnomad4 ASJ AF: 0.00866

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00536

Gnomad4 NFE AF: 0.0211

Gnomad4 OTH AF: 0.0616

Alfa AF: 0.0337 Hom.: 363

Bravo AF: 0.0841

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.0205

EpiControl AF: 0.0199

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.66

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: rs16868675; hg19: chr5-16481185; COSMIC: COSV104626867; COSMIC: COSV104626867;