rs78314670

Positions:

• chr5-16572044-G-A
• chr5-16572044-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001034850.3(RETREG1):​c.379C>T​(p.Arg127Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00723 in 1,613,468 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (52 hom.)
• Consequence: RETREG1 NM_001034850.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.73

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=0.009130418).
• BP6: Variant 5-16572044-G-A is Benign according to our data. Variant chr5-16572044-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-16572044-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00572 (870/152102) while in subpopulation NFE AF= 0.00799 (543/67998). AF 95% confidence interval is 0.00743. There are 4 homozygotes in gnomad4. There are 452 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RETREG1	NM_001034850.3	c.379C>T	p.Arg127Cys	missense_variant	2/9	ENST00000306320.10
RETREG1	XM_011514053.4	c.379C>T	p.Arg127Cys	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RETREG1	ENST00000306320.10	c.379C>T	p.Arg127Cys	missense_variant	2/9	1	NM_001034850.3

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 870 AN: 151984 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00798

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00642 AC: 1602 AN: 249488 Hom.: 7 AF XY: 0.00624 AC XY: 845 AN XY: 135352

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.00956

Gnomad OTH exome AF: 0.00793

GnomAD4 exome AF: 0.00739 AC: 10799 AN: 1461366 Hom.: 52 Cov.: 30 AF XY: 0.00709 AC XY: 5156 AN XY: 727034

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.00842

Gnomad4 OTH exome AF: 0.00654

GnomAD4 genome AF: 0.00572 AC: 870 AN: 152102 Hom.: 4 Cov.: 32 AF XY: 0.00608 AC XY: 452 AN XY: 74378

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0180

Gnomad4 NFE AF: 0.00799

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00673 Hom.: 7

Bravo AF: 0.00437

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.000806 AC: 3

ESP6500EA AF: 0.00792 AC: 65

ExAC AF: 0.00700 AC: 846

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RETREG1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

RETREG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2016

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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.079
Sift	Benign	0.16	T
Sift4G	Benign	0.21	T
Polyphen		0.027	B
Vest4		0.43
MVP		0.47
MPC		0.45
ClinPred		0.016	T
GERP RS		4.0
Varity_R		0.058
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs78314670; hg19: chr5-16572153;