rs61733811

Variant names:

• chr5-16475090-C-G
• rs61733811
• NM_001034850.3:c.1145G>C

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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:5
• Conservation: PhyloP100: 0.634
• Publications: 5 publications found

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]

RETREG1 Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory and autonomic, type 2B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289112 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 21256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034850.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	NM_001034850.3	MANE Select	c.1145G>C	p.Ser382Thr	missense	Exon 9 of 9	NP_001030022.1	Q9H6L5-1
	RETREG1	NM_019000.5		c.722G>C	p.Ser241Thr	missense	Exon 7 of 7	NP_061873.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.1145G>C	p.Ser382Thr	missense	Exon 9 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000399793.6	TSL:1	c.722G>C	p.Ser241Thr	missense	Exon 7 of 7	ENSP00000382691.2	Q9H6L5-2
	RETREG1	ENST00000510362.6	TSL:1	n.620G>C		non_coding_transcript_exon	Exon 7 of 8	ENSP00000425089.2	H0Y9U4

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

GnomAD2 exomes AF: 0.00818 AC: 2037 AN: 248902 AF XY: 0.00616

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 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

African (AFR) AF: 0.111 AC: 3705 AN: 33466

American (AMR) AF: 0.00656 AC: 293 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 60 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5762

European-Non Finnish (NFE) AF: 0.000361 AC: 401 AN: 1111918

Other (OTH) AF: 0.00922 AC: 557 AN: 60392

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

African (AFR) AF: 0.107 AC: 4464 AN: 41542

American (AMR) AF: 0.0115 AC: 176 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68024

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Neuropathy, hereditary sensory and autonomic, type 2B (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.63
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.082
Sift	Benign	0.30	T
Sift4G	Benign	0.45	T
Polyphen		0.011	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
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: rs61733811; hg19: chr5-16475199;