NM_001034850.3:c.607G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001034850.3(RETREG1):c.607G>A(p.Val203Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0046 in 1,611,312 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 17 hom. )

Consequence

RETREG1
NM_001034850.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.214

Publications

5 publications found

Variant links:

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):

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

RETREG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011584997).

BP6

Variant 5-16481072-C-T is Benign according to our data. Variant chr5-16481072-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 245600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00297 (452/152070) while in subpopulation NFE AF = 0.00496 (337/67948). AF 95% confidence interval is 0.00452. There are 2 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RETREG1	NM_001034850.3 link	c.607G>A	p.Val203Met	missense_variant	Exon 5 of 9	ENST00000306320.10	NP_001030022.1	Q9H6L5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RETREG1	ENST00000306320.10 link	c.607G>A	p.Val203Met	missense_variant	Exon 5 of 9	1	NM_001034850.3	ENSP00000304642.9		Q9H6L5-1

Frequencies

GnomAD3 genomes

AF:

0.00297

AC:

452

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000701

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00328

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00496

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00324

AC:

806

AN:

248472

AF XY:

0.00341

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.00317

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00252

Gnomad NFE exome

AF:

0.00464

Gnomad OTH exome

AF:

0.00466

GnomAD4 exome

AF:

0.00477

AC:

6964

AN:

1459242

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

3388

AN XY:

726002

show subpopulations

African (AFR)

AF:

0.000809

AC:

AN:

33384

American (AMR)

AF:

0.00323

AC:

144

AN:

44586

Ashkenazi Jewish (ASJ)

AF:

0.000422

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.00291

AC:

251

AN:

86214

European-Finnish (FIN)

AF:

0.00313

AC:

167

AN:

53308

Middle Eastern (MID)

AF:

0.00244

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00547

AC:

6076

AN:

1110056

Other (OTH)

AF:

0.00455

AC:

274

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

324

647

971

1294

1618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

242

484

726

968

1210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00297

AC:

452

AN:

152070

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000699

AC:

AN:

41496

American (AMR)

AF:

0.00328

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00270

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00496

AC:

337

AN:

67948

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00403

Hom.:

Bravo

AF:

0.00309

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00105

AC:

ESP6500EA

AF:

0.00438

AC:

ExAC

AF:

0.00334

AC:

404

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00426

EpiControl

AF:

0.00445

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RETREG1: BS2 -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuropathy, hereditary sensory and autonomic, type 2B

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 15, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.17

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

.;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.32

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.77

PhyloP100

0.21

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.17

Sift

Benign

0.066

T;T

Sift4G

Benign

0.11

T;T

Polyphen

1.0

D;D

Vest4

0.27

MVP

0.47

MPC

1.0

ClinPred

0.015

GERP RS

5.1

Varity_R

0.12

gMVP

0.40

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over