dbSNP rs375491312: DERL3:p.Phe71Cys (chr22-23838585-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001002862.3(DERL3):c.212T>G(p.Phe71Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,588,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

DERL3
NM_001002862.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87

Variant links:

Genes affected

DERL3 (HGNC:14236): (derlin 3) The protein encoded by this gene belongs to the derlin family, and resides in the endoplasmic reticulum (ER). Proteins that are unfolded or misfolded in the ER must be refolded or degraded to maintain the homeostasis of the ER. This protein appears to be involved in the degradation of misfolded glycoproteins in the ER. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]

DERL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DERL3	NM_001002862.3 link	c.212T>G	p.Phe71Cys	missense_variant	Exon 3 of 7	ENST00000318109.12	NP_001002862.1	Q96Q80-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DERL3	ENST00000318109.12 link	c.212T>G	p.Phe71Cys	missense_variant	Exon 3 of 7	1	NM_001002862.3	ENSP00000315303.8		Q96Q80-1

Frequencies

GnomAD3 genomes

AF:

0.000160

AC:

AN:

150406

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

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:

0.000341

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

211884

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

114484

show subpopulations

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 SAS exome

AF:

0.0000374

Gnomad FIN exome

AF:

0.000167

Gnomad NFE exome

AF:

0.000192

Gnomad OTH exome

AF:

0.000187

GnomAD4 exome

AF:

0.000143

AC:

205

AN:

1438436

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

106

AN XY:

713466

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.000175

Gnomad4 NFE exome

AF:

0.000173

Gnomad4 OTH exome

AF:

0.0000841

GnomAD4 genome

AF:

0.000160

AC:

AN:

150406

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

73378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000341

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000354

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000133

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.212T>G (p.F71C) alteration is located in exon 3 (coding exon 3) of the DERL3 gene. This alteration results from a T to G substitution at nucleotide position 212, causing the phenylalanine (F) at amino acid position 71 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;T;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Benign

-0.56

MutationAssessor

Pathogenic

4.2

H;H;H

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.2

D;D;D

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.90

MVP

0.70

MPC

0.66

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over