22-23838588-C-A

Variant names:

• chr22-23838588-C-A
• rs368825157
• NM_001002862.3:c.209G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001002862.3(DERL3):​c.209G>T​(p.Ser70Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,589,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 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: 0.0000042 (0 hom.)
• Consequence: DERL3 NM_001002862.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.696
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3077184).

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.209G>T	p.Ser70Ile	missense	Exon 3 of 7	NP_001002862.1	Q96Q80-1
	DERL3	NM_001135751.2		c.209G>T	p.Ser70Ile	missense	Exon 3 of 7	NP_001129223.1	Q96Q80-2
	DERL3	NM_001363072.2		c.209G>T	p.Ser70Ile	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.209G>T	p.Ser70Ile	missense	Exon 3 of 7	ENSP00000315303.8	Q96Q80-1
	DERL3	ENST00000406855.7	TSL:1	c.209G>T	p.Ser70Ile	missense	Exon 3 of 7	ENSP00000384744.3	Q96Q80-2
	DERL3	ENST00000476077.1	TSL:1	c.209G>T	p.Ser70Ile	missense	Exon 3 of 6	ENSP00000419399.1	Q96Q80-5

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150678 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000489

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 211736 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1439306 Hom.: 0 Cov.: 36 AF XY: 0.00000420 AC XY: 3 AN XY: 713890

African (AFR) AF: 0.00 AC: 0 AN: 32886

American (AMR) AF: 0.00 AC: 0 AN: 41454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 38184

South Asian (SAS) AF: 0.00 AC: 0 AN: 82808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000545 AC: 6 AN: 1101366

Other (OTH) AF: 0.00 AC: 0 AN: 59546

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150678 Hom.: 0 Cov.: 32 AF XY: 0.0000272 AC XY: 2 AN XY: 73436

African (AFR) AF: 0.0000489 AC: 2 AN: 40914

American (AMR) AF: 0.00 AC: 0 AN: 15000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10276

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67864

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0088	T
Eigen	Benign	0.073
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.2	T
PhyloP100		0.70
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.038
Sift	Benign	0.53	T
Sift4G	Benign	0.54	T
Vest4		0.32
MutPred		0.40		Gain of catalytic residue at L76 (P = 0.0843)
MVP		0.61
ClinPred		0.98	D
GERP RS		3.1
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
Mutation Taster		=79/21	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: rs368825157; hg19: chr22-24180775;