rs759050645

Variant names:

• chr5-16616950-C-A
• rs759050645
• NM_001034850.3:c.22G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-16616950-C-A
• chr5-16616950-C-G
• chr5-16616950-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001034850.3(RETREG1):​c.22G>T​(p.Glu8*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 1,292,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E8E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69
• Publications: 0 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-AS1 (HGNC:55551): (RETREG1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.22G>T	p.Glu8*	stop_gained	Exon 1 of 9	NP_001030022.1	Q9H6L5-1
	RETREG1-AS1	NR_109946.1		n.561+464C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.22G>T	p.Glu8*	stop_gained	Exon 1 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000682229.1		c.22G>T	p.Glu8*	stop_gained	Exon 1 of 10	ENSP00000507342.1	A0A804HJ37
	RETREG1	ENST00000682564.1		c.22G>T	p.Glu8*	stop_gained	Exon 1 of 9	ENSP00000508099.1	A0A804HKW5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000155 AC: 2 AN: 1292838 Hom.: 0 Cov.: 29 AF XY: 0.00000157 AC XY: 1 AN XY: 635720

African (AFR) AF: 0.00 AC: 0 AN: 26026

American (AMR) AF: 0.00 AC: 0 AN: 23438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22104

East Asian (EAS) AF: 0.00 AC: 0 AN: 27938

South Asian (SAS) AF: 0.00 AC: 0 AN: 68282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3826

European-Non Finnish (NFE) AF: 0.00000193 AC: 2 AN: 1035922

Other (OTH) AF: 0.00 AC: 0 AN: 53302

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.039	N
PhyloP100		1.7
Vest4		0.089
GERP RS		3.0
PromoterAI		0.14	Neutral
Mutation Taster		=18/182	disease causing (fs/PTC)

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: rs759050645; hg19: chr5-16617059;