NM_001002862.3:c.226C>T

Variant names:

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

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>T​(p.Leu76Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,435,278 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L76V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DERL3 NM_001002862.3 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.25421804).

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>T	p.Leu76Phe	missense	Exon 3 of 7	NP_001002862.1	Q96Q80-1
	DERL3	NM_001135751.2		c.226C>T	p.Leu76Phe	missense	Exon 3 of 7	NP_001129223.1	Q96Q80-2
	DERL3	NM_001363072.2		c.226C>T	p.Leu76Phe	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>T	p.Leu76Phe	missense	Exon 3 of 7	ENSP00000315303.8	Q96Q80-1
	DERL3	ENST00000406855.7	TSL:1	c.226C>T	p.Leu76Phe	missense	Exon 3 of 7	ENSP00000384744.3	Q96Q80-2
	DERL3	ENST00000476077.1	TSL:1	c.226C>T	p.Leu76Phe	missense	Exon 3 of 6	ENSP00000419399.1	Q96Q80-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435278 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 711588

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

American (AMR) AF: 0.00 AC: 0 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: 0.00000182 AC: 2 AN: 1099290

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.079
Eigen_PC	Benign	0.094
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.3
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.24
Sift	Benign	0.23	T
Sift4G	Benign	0.22	T
Vest4		0.40
MutPred		0.36		Loss of helix (P = 0.0017)
MVP		0.63
ClinPred		0.50	D
GERP RS		4.2
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;