NM_001002862.3:c.226C>G

Variant names:

• chr22-23838571-G-C
• rs758963009
• NM_001002862.3:c.226C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001002862.3(DERL3):​c.226C>G​(p.Leu76Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000063 in 1,586,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: DERL3 NM_001002862.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.31
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19948465).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002862.3. 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
	DERL3	NM_001002862.3	MANE Select	c.226C>G	p.Leu76Val	missense	Exon 3 of 7	NP_001002862.1	Q96Q80-1
	DERL3	NM_001135751.2		c.226C>G	p.Leu76Val	missense	Exon 3 of 7	NP_001129223.1	Q96Q80-2
	DERL3	NM_001363072.2		c.226C>G	p.Leu76Val	missense	Exon 3 of 7	NP_001350001.1	Q96Q80-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DERL3	ENST00000318109.12	TSL:1 MANE Select	c.226C>G	p.Leu76Val	missense	Exon 3 of 7	ENSP00000315303.8	Q96Q80-1
	DERL3	ENST00000406855.7	TSL:1	c.226C>G	p.Leu76Val	missense	Exon 3 of 7	ENSP00000384744.3	Q96Q80-2
	DERL3	ENST00000476077.1	TSL:1	c.226C>G	p.Leu76Val	missense	Exon 3 of 6	ENSP00000419399.1	Q96Q80-5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151310 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000243 AC: 5 AN: 205416 AF XY: 0.0000271

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000667

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000333

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000557 AC: 8 AN: 1435278 Hom.: 0 Cov.: 36 AF XY: 0.00000703 AC XY: 5 AN XY: 711588

African (AFR) AF: 0.00 AC: 0 AN: 32762

American (AMR) AF: 0.0000490 AC: 2 AN: 40782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25670

East Asian (EAS) AF: 0.00 AC: 0 AN: 37878

South Asian (SAS) AF: 0.00 AC: 0 AN: 82402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000546 AC: 6 AN: 1099290

Other (OTH) AF: 0.00 AC: 0 AN: 59388

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151310 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73864

African (AFR) AF: 0.00 AC: 0 AN: 41212

American (AMR) AF: 0.00 AC: 0 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67804

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	0.032
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.3
PROVEAN	Benign	0.31	N
REVEL	Benign	0.055
Sift	Benign	0.76	T
Sift4G	Benign	0.63	T
Vest4		0.36
MVP		0.71
ClinPred		0.13	T
GERP RS		4.2
PromoterAI		0.12	Neutral
Varity_R		0.12
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs758963009; hg19: chr22-24180758;