rs758081460

Positions:

• chr5-16474779-ACTT-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PM4_Supporting BS1_Supporting

The NM_001034850.3(RETREG1):​c.1453_1455del​(p.Lys485del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,612,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.17

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001034850.3. Strenght limited to Supporting due to length of the change: 1aa.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000232 (35/150718) while in subpopulation AFR AF= 0.00083 (34/40978). AF 95% confidence interval is 0.00061. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RETREG1	NM_001034850.3	c.1453_1455del	p.Lys485del	inframe_deletion	9/9	ENST00000306320.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RETREG1	ENST00000306320.10	c.1453_1455del	p.Lys485del	inframe_deletion	9/9	1	NM_001034850.3

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 35 AN: 150604 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000361 AC: 9 AN: 249014 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135168

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461478 Hom.: 0 AF XY: 0.0000165 AC XY: 12 AN XY: 727060

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000232 AC: 35 AN: 150718 Hom.: 0 Cov.: 31 AF XY: 0.000231 AC XY: 17 AN XY: 73490

Gnomad4 AFR AF: 0.000830

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000272

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 10, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2020

The c.1453_1455delAAG variant (also known as p.K485del) is located in coding exon 9 of the FAM134B gene. This variant results from an in-frame deletion of 3 nucleotides at nucleotide positions 1453 to 1455. This results in an in-frame deletion of a lysine residue at codon 485. This amino acid position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 26, 2021

This variant, c.1453_1455del, results in the deletion of 1 amino acid(s) of the RETREG1 protein (p.Lys485del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758081460, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with RETREG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 439686). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs758081460; hg19: chr5-16474888;