rs137852738

Variant names:

• chr5-16478032-A-G
• rs137852738
• NM_001034850.3:c.873+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001034850.3(RETREG1):​c.873+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RETREG1 NM_001034850.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9594
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:2
• Conservation: PhyloP100: 4.56
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-16478032-A-G is Pathogenic according to our data. Variant chr5-16478032-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 21259.Status of the report is criteria_provided_single_submitter, 1 stars.

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.873+2T>C		splice_donor intron	N/A	NP_001030022.1	Q9H6L5-1
	RETREG1	NM_019000.5		c.450+2T>C		splice_donor intron	N/A	NP_061873.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.873+2T>C		splice_donor intron	N/A	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000399793.6	TSL:1	c.450+2T>C		splice_donor intron	N/A	ENSP00000382691.2	Q9H6L5-2
	RETREG1	ENST00000510362.6	TSL:1	n.348+2T>C		splice_donor intron	N/A	ENSP00000425089.2	H0Y9U4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease (1)
-	1	-	Hereditary sensory and autonomic neuropathy type 2 (1)
1	-	-	Neuropathy, hereditary sensory and autonomic, type 2B (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Benign	0.85
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		4.6
GERP RS		4.4
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.58
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137852738; hg19: chr5-16478141;