rs61733811

chr5-16475090-C-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.1145G>C(p.Ser382Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00612 in 1,613,976 control chromosomes in the GnomAD database, including 481 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (253 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (228 hom.)
• Consequence: RETREG1 NM_001034850.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.634

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 (MetaRNN=0.0015785694).
• BP6: Variant 5-16475090-C-G is Benign according to our data. Variant chr5-16475090-C-G is described in ClinVar as [Benign]. Clinvar id is 21256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-16475090-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RETREG1	NM_001034850.3	c.1145G>C	p.Ser382Thr	missense_variant	9/9	ENST00000306320.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RETREG1	ENST00000306320.10	c.1145G>C	p.Ser382Thr	missense_variant	9/9	1	NM_001034850.3

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4722 AN: 152160 Hom.: 250 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.00818 AC: 2037 AN: 248902 Hom.: 104 AF XY: 0.00616 AC XY: 832 AN XY: 135040

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000789

Gnomad OTH exome AF: 0.00563

GnomAD4 exome AF: 0.00351 AC: 5128 AN: 1461698 Hom.: 228 Cov.: 35 AF XY: 0.00307 AC XY: 2234 AN XY: 727154

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.00656

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000361

Gnomad4 OTH exome AF: 0.00922

GnomAD4 genome AF: 0.0312 AC: 4756 AN: 152278 Hom.: 253 Cov.: 31 AF XY: 0.0298 AC XY: 2218 AN XY: 74460

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.00522 Hom.: 22

Bravo AF: 0.0362

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.102 AC: 405

ESP6500EA AF: 0.000599 AC: 5

ExAC AF: 0.00973 AC: 1176

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.000948

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

Sep 14, 2015

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

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Benign	0.57
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.082
Sift	Benign	0.30	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.011	B;B
Vest4		0.049
MVP		0.45
MPC		0.32
ClinPred		0.0025	T
GERP RS		5.0
Varity_R		0.076
gMVP		0.15

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: rs61733811; hg19: chr5-16475199;