rs750740230

chr5-16616966-C-Gchr5-16616966-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6 BP7 BS1

The NM_001034850.3(RETREG1):c.6G>C(p.Ala2=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,429,166 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.16

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-16616966-C-G is Benign according to our data. Variant chr5-16616966-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 352698.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr5-16616966-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000409 (62/151688) while in subpopulation NFE AF= 0.000618 (42/67908). AF 95% confidence interval is 0.00047. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RETREG1	NM_001034850.3	c.6G>C	p.Ala2=	synonymous_variant	1/9	ENST00000306320.10
RETREG1-AS1	NR_109946.1	n.561+480C>G		intron_variant, non_coding_transcript_variant
RETREG1	XM_011514053.4	c.6G>C	p.Ala2=	synonymous_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RETREG1	ENST00000306320.10	c.6G>C	p.Ala2=	synonymous_variant	1/9	1	NM_001034850.3
RETREG1-AS1	ENST00000653650.1	n.329+480C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000409 AC: 62 AN: 151688 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000341 AC: 21 AN: 61560 Hom.: 0 AF XY: 0.000335 AC XY: 12 AN XY: 35790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000436

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: 0.000696

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000672 AC: 859 AN: 1277478 Hom.: 0 Cov.: 29 AF XY: 0.000674 AC XY: 423 AN XY: 627642

Gnomad4 AFR exome AF: 0.0000777

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0000465

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000948

Gnomad4 NFE exome AF: 0.000787

Gnomad4 OTH exome AF: 0.000647

GnomAD4 genome AF: 0.000409 AC: 62 AN: 151688 Hom.: 0 Cov.: 32 AF XY: 0.000419 AC XY: 31 AN XY: 74066

Gnomad4 AFR AF: 0.000218

Gnomad4 AMR AF: 0.000525

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000192

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000465

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	- -

Neuropathy, hereditary sensory and autonomic, type 2B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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	-0.43
Cadd	Benign	16
Dann	Benign	0.69

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: rs750740230; hg19: chr5-16617075;