rs1554022467

Variant names:

• chr5-16565764-T-C
• rs1554022467
• NM_001034850.3:c.457A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001034850.3(RETREG1):​c.457A>G​(p.Ser153Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.32
• 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):

• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.457A>G	p.Ser153Gly	missense splice_region	Exon 3 of 9	NP_001030022.1	Q9H6L5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.457A>G	p.Ser153Gly	missense splice_region	Exon 3 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000682229.1		c.457A>G	p.Arg153Gly	missense splice_region	Exon 3 of 10	ENSP00000507342.1	A0A804HJ37
	RETREG1	ENST00000682564.1		c.457A>G	p.Ser153Gly	missense splice_region	Exon 3 of 9	ENSP00000508099.1	A0A804HKW5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461608 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727094

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.035	D
Polyphen		0.83	P
Vest4		0.28
MutPred		0.30		Gain of sheet (P = 0.0266)
MVP		0.50
MPC		0.67
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.32
gMVP		0.27
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.64		Position offset: -1

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

Other links and lift over

dbSNP: rs1554022467; hg19: chr5-16565873;