chr5-16616950-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001034850.3(RETREG1):c.22G>A(p.Glu8Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,444,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E8Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

RETREG1
NM_001034850.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.69

Publications

0 publications found

Variant links:

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 links:

RETREG1-AS1 (HGNC:55551): (RETREG1 antisense RNA 1)

RETREG1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07861903).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000211 (32/151890) while in subpopulation AFR AF = 0.000458 (19/41516). AF 95% confidence interval is 0.000299. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.22G>A	p.Glu8Lys	missense	Exon 1 of 9	NP_001030022.1	Q9H6L5-1
	RETREG1-AS1	NR_109946.1		n.561+464C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.22G>A	p.Glu8Lys	missense	Exon 1 of 9	ENSP00000304642.9	Q9H6L5-1
RETREG1	ENST00000682229.1		c.22G>A	p.Glu8Lys	missense	Exon 1 of 10	ENSP00000507342.1	A0A804HJ37
RETREG1	ENST00000682564.1		c.22G>A	p.Glu8Lys	missense	Exon 1 of 9	ENSP00000508099.1	A0A804HKW5

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

151784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000149

AC:

AN:

67192

AF XY:

0.000153

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000325

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000136

AC:

176

AN:

1292836

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

635716

show subpopulations

African (AFR)

AF:

0.000231

AC:

AN:

26026

American (AMR)

AF:

0.000299

AC:

AN:

23436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22104

East Asian (EAS)

AF:

0.00

AC:

AN:

27938

South Asian (SAS)

AF:

0.000117

AC:

AN:

68284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3826

European-Non Finnish (NFE)

AF:

0.000145

AC:

150

AN:

1035920

Other (OTH)

AF:

0.0000938

AC:

AN:

53302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000211

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41516

American (AMR)

AF:

0.000197

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67896

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000242

ExAC

AF:

0.0000459

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Neuropathy, hereditary sensory and autonomic, type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0054

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.53

M_CAP

Benign

0.073

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.0

PhyloP100

1.7

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.36

REVEL

Benign

0.039

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.20

Vest4

0.15

MutPred

0.21

Gain of methylation at E8 (P = 8e-04)

MVP

0.41

MPC

0.37

ClinPred

0.19

GERP RS

3.0

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.074

gMVP

0.28

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over