5-16616886-G-A

Variant names:

• chr5-16616886-G-A
• rs528532732
• NM_001034850.3:c.86C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001034850.3(RETREG1):​c.86C>T​(p.Pro29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,484,994 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. P29P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: RETREG1 NM_001034850.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.25
• Publications: 2 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-AS1 (HGNC:55551): (RETREG1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006113887).
• BP6: Variant 5-16616886-G-A is Benign according to our data. Variant chr5-16616886-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 538126.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000322 (49/152132) while in subpopulation EAS AF = 0.00681 (35/5140). AF 95% confidence interval is 0.00503. There are 3 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	NM_001034850.3	MANE Select	c.86C>T	p.Pro29Leu	missense	Exon 1 of 9	NP_001030022.1
	RETREG1-AS1	NR_109946.1		n.561+400G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.86C>T	p.Pro29Leu	missense	Exon 1 of 9	ENSP00000304642.9
	RETREG1	ENST00000682229.1		c.86C>T	p.Pro29Leu	missense	Exon 1 of 10	ENSP00000507342.1
	RETREG1	ENST00000682564.1		c.86C>T	p.Pro29Leu	missense	Exon 1 of 9	ENSP00000508099.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152022 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00679

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000223 AC: 19 AN: 85362 AF XY: 0.000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000321

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000409 AC: 545 AN: 1332862 Hom.: 4 Cov.: 29 AF XY: 0.000423 AC XY: 278 AN XY: 656884

African (AFR) AF: 0.000335 AC: 9 AN: 26882

American (AMR) AF: 0.0000347 AC: 1 AN: 28812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23574

East Asian (EAS) AF: 0.0169 AC: 506 AN: 29864

South Asian (SAS) AF: 0.000162 AC: 12 AN: 74040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4116

European-Non Finnish (NFE) AF: 0.00000757 AC: 8 AN: 1057120

Other (OTH) AF: 0.000162 AC: 9 AN: 55388

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152132 Hom.: 3 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74376

African (AFR) AF: 0.000241 AC: 10 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00681 AC: 35 AN: 5140

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000238

ExAC AF: 0.0000852 AC: 2

Asia WGS AF: 0.00291 AC: 10 AN: 3456

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Jan 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge

Aug 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 25, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FAM134B (aka RETREG1) c.86C>T; p.Pro29Leu variant (rs528532732), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an East Asian population frequency of 0.3% (identified on 15 out of 5840 chromosomes). The proline at position 29 is weakly conserved, considering 11 species, and computational analyses of the effects of the p.Pro29Leu variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Pro29Leu variant cannot be determined with certainty.

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 16, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.027
Sift	Benign	0.20	T
Sift4G	Benign	0.14	T
Polyphen		0.16	B
Vest4		0.28
MutPred		0.24		Loss of glycosylation at P29 (P = 9e-04)
MVP		0.23
MPC		0.34
ClinPred		0.023	T
GERP RS		-0.27
PromoterAI		-0.012	Neutral
Varity_R		0.031
gMVP		0.19
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs528532732; hg19: chr5-16616995; COSMIC: COSV60448785; COSMIC: COSV60448785;