rs34432513

Variant names:

• chr5-16475100-G-C
• rs34432513
• NM_001034850.3:c.1135C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001034850.3(RETREG1):​c.1135C>G​(p.Gln379Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00205 in 1,613,924 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. Q379H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (31 hom.)
• Consequence: RETREG1 NM_001034850.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.12
• 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=0.002496004).
• BP6: Variant 5-16475100-G-C is Benign according to our data. Variant chr5-16475100-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1607/152232) while in subpopulation AFR AF = 0.0358 (1486/41538). AF 95% confidence interval is 0.0343. There are 24 homozygotes in GnomAd4. There are 784 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

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.1135C>G	p.Gln379Glu	missense	Exon 9 of 9	NP_001030022.1
	RETREG1	NM_019000.5		c.712C>G	p.Gln238Glu	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.1135C>G	p.Gln379Glu	missense	Exon 9 of 9	ENSP00000304642.9
	RETREG1	ENST00000399793.6	TSL:1	c.712C>G	p.Gln238Glu	missense	Exon 7 of 7	ENSP00000382691.2
	RETREG1	ENST00000510362.6	TSL:1	n.610C>G		non_coding_transcript_exon	Exon 7 of 8	ENSP00000425089.2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1601 AN: 152114 Hom.: 25 Cov.: 31

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00266 AC: 663 AN: 248972 AF XY: 0.00218

Gnomad AFR exome AF: 0.0367

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00116 AC: 1694 AN: 1461692 Hom.: 31 Cov.: 35 AF XY: 0.00103 AC XY: 750 AN XY: 727154

African (AFR) AF: 0.0391 AC: 1310 AN: 33464

American (AMR) AF: 0.00184 AC: 82 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5762

European-Non Finnish (NFE) AF: 0.0000935 AC: 104 AN: 1111908

Other (OTH) AF: 0.00258 AC: 156 AN: 60392

GnomAD4 genome AF: 0.0106 AC: 1607 AN: 152232 Hom.: 24 Cov.: 31 AF XY: 0.0105 AC XY: 784 AN XY: 74444

African (AFR) AF: 0.0358 AC: 1486 AN: 41538

American (AMR) AF: 0.00549 AC: 84 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68004

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00155 Hom.: 3

Bravo AF: 0.0121

ESP6500AA AF: 0.0347 AC: 137

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00329 AC: 398

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Neuropathy, hereditary sensory and autonomic, type 2B (2)
-	-	2	not provided (2)
-	-	1	Neuropathy, hereditary sensory and autonomic, type 2B;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.14
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.1
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.034	B
Vest4		0.20
MVP		0.38
MPC		0.39
ClinPred		0.0066	T
GERP RS		3.9
Varity_R		0.045
gMVP		0.11
Mutation Taster		=100/0	polymorphism

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: rs34432513; hg19: chr5-16475209;