rs773314283

Positions:

• chr5-16616954-A-C
• chr5-16616954-A-G
• chr5-16616954-A-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001034850.3(RETREG1):​c.18T>G​(p.Pro6Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,438,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.593

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

Verdict is Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-16616954-A-C is Benign according to our data. Variant chr5-16616954-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 538137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.593 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000171 (26/151614) while in subpopulation NFE AF= 0.000324 (22/67894). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RETREG1	NM_001034850.3	c.18T>G	p.Pro6Pro	synonymous_variant	1/9	ENST00000306320.10	NP_001030022.1
RETREG1	XM_011514053.4	c.18T>G	p.Pro6Pro	synonymous_variant	1/10		XP_011512355.1
RETREG1-AS1	NR_109946.1	n.561+468A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RETREG1	ENST00000306320.10	c.18T>G	p.Pro6Pro	synonymous_variant	1/9	1	NM_001034850.3	ENSP00000304642.9

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151614 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 11 AN: 66608 Hom.: 0 AF XY: 0.0000774 AC XY: 3 AN XY: 38778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000818

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.000522

GnomAD4 exome AF: 0.000432 AC: 556 AN: 1286422 Hom.: 0 Cov.: 29 AF XY: 0.000433 AC XY: 274 AN XY: 632624

Gnomad4 AFR exome AF: 0.000154

Gnomad4 AMR exome AF: 0.0000857

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000251

Gnomad4 SAS exome AF: 0.0000147

Gnomad4 FIN exome AF: 0.0000626

Gnomad4 NFE exome AF: 0.000502

Gnomad4 OTH exome AF: 0.000434

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151614 Hom.: 0 Cov.: 32 AF XY: 0.000149 AC XY: 11 AN XY: 74022

Gnomad4 AFR AF: 0.0000968

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000200

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.4
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs773314283; hg19: chr5-16617063; COSMIC: COSV60448846; COSMIC: COSV60448846;