rs334493

Variant names:

• chr5-16528148-T-C
• rs334493
• NM_001034850.3:c.458+37615A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001034850.3(RETREG1):​c.458+37615A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 152,152 control chromosomes in the GnomAD database, including 1,130 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1130 hom., cov: 31)
• Consequence: RETREG1 NM_001034850.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 3 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):

• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RETREG1	NM_001034850.3	c.458+37615A>G		intron_variant	Intron 3 of 8	ENST00000306320.10	NP_001030022.1
RETREG1	XM_011514053.4	c.459-22625A>G		intron_variant	Intron 3 of 9		XP_011512355.1
RETREG1	XM_011514055.4	c.59+14153A>G		intron_variant	Intron 1 of 6		XP_011512357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RETREG1	ENST00000306320.10	c.458+37615A>G		intron_variant	Intron 3 of 8	1	NM_001034850.3	ENSP00000304642.9

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17092 AN: 152034 Hom.: 1130 Cov.: 31

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.0854

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.0748

Gnomad FIN AF: 0.0450

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.117

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.112 AC: 17111 AN: 152152 Hom.: 1130 Cov.: 31 AF XY: 0.109 AC XY: 8073 AN XY: 74370

African (AFR) AF: 0.157 AC: 6503 AN: 41490

American (AMR) AF: 0.0852 AC: 1303 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3470

East Asian (EAS) AF: 0.0172 AC: 89 AN: 5170

South Asian (SAS) AF: 0.0757 AC: 365 AN: 4820

European-Finnish (FIN) AF: 0.0450 AC: 476 AN: 10586

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7557 AN: 68010

Other (OTH) AF: 0.117 AC: 246 AN: 2108

Alfa AF: 0.114 Hom.: 1777

Bravo AF: 0.119

Asia WGS AF: 0.0480 AC: 169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.67
DANN	Benign	0.35
PhyloP100		-1.4
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: rs334493; hg19: chr5-16528257;