rs760751442

Variant names:

• chr5-16478057-C-A
• rs760751442
• NM_001034850.3:c.850G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001034850.3(RETREG1):​c.850G>T​(p.Asp284Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000617 in 1,458,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D284D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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.850G>T	p.Asp284Tyr	missense	Exon 7 of 9	NP_001030022.1
	RETREG1	NM_019000.5		c.427G>T	p.Asp143Tyr	missense	Exon 5 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.850G>T	p.Asp284Tyr	missense	Exon 7 of 9	ENSP00000304642.9
	RETREG1	ENST00000399793.6	TSL:1	c.427G>T	p.Asp143Tyr	missense	Exon 5 of 7	ENSP00000382691.2
	RETREG1	ENST00000510362.6	TSL:1	n.325G>T		non_coding_transcript_exon	Exon 5 of 8	ENSP00000425089.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245244 AF XY: 0.00000752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458102 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725260

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.00 AC: 0 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 85618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000811 AC: 9 AN: 1109980

Other (OTH) AF: 0.00 AC: 0 AN: 60214

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000166 AC: 2

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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.44	T
PhyloP100		5.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.31		Loss of disorder (P = 0.0078)
MVP		0.87
MPC		1.2
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.48
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs760751442; hg19: chr5-16478166;