rs1554014585

Variant names:

• chr5-16474857-G-C
• rs1554014585
• NM_001034850.3:c.1378C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001034850.3(RETREG1):​c.1378C>G​(p.Gln460Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q460H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RETREG1 NM_001034850.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.98
• 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 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

ENSG00000289112 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

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.1378C>G	p.Gln460Glu	missense	Exon 9 of 9	NP_001030022.1
	RETREG1	NM_019000.5		c.955C>G	p.Gln319Glu	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.1378C>G	p.Gln460Glu	missense	Exon 9 of 9	ENSP00000304642.9
	RETREG1	ENST00000399793.6	TSL:1	c.955C>G	p.Gln319Glu	missense	Exon 7 of 7	ENSP00000382691.2
	RETREG1	ENST00000510362.6	TSL:1	n.853C>G		non_coding_transcript_exon	Exon 7 of 8	ENSP00000425089.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.15	D
PhyloP100		9.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.77
MutPred		0.42		Gain of relative solvent accessibility (P = 0.0289)
MVP		0.93
MPC		1.1
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.73
gMVP		0.23
Mutation Taster		=31/69	disease causing

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: rs1554014585; hg19: chr5-16474966;