8-123015580-C-A

Variant names:

• chr8-123015580-C-A
• rs141975370
• NM_024295.6:c.623G>T

Variant summary

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

The NM_024295.6(DERL1):​c.623G>T​(p.Arg208Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,452 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R208H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DERL1 NM_024295.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.53
• Publications: 0 publications found

Genes affected

DERL1 (HGNC:28454): (derlin 1) The protein encoded by this gene is a member of the derlin family. Members of this family participate in the ER-associated degradation response and retrotranslocate misfolded or unfolded proteins from the ER lumen to the cytosol for proteasomal degradation. This protein recognizes substrate in the ER and works in a complex to retrotranslocate it across the ER membrane into the cytosol. This protein may select cystic fibrosis transmembrane conductance regulator protein (CFTR) for degradation as well as unfolded proteins in Alzheimer's disease. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Aug 2012]

ENSG00000253607 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024295.6. 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
	DERL1	NM_024295.6	MANE Select	c.623G>T	p.Arg208Leu	missense	Exon 8 of 8	NP_077271.1	Q9BUN8-1
	DERL1	NM_001134671.3		c.563G>T	p.Arg188Leu	missense	Exon 8 of 8	NP_001128143.1	Q9BUN8-2
	DERL1	NM_001330601.2		c.323G>T	p.Arg108Leu	missense	Exon 7 of 7	NP_001317530.1	E5RGY0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DERL1	ENST00000259512.9	TSL:1 MANE Select	c.623G>T	p.Arg208Leu	missense	Exon 8 of 8	ENSP00000259512.3	Q9BUN8-1
	DERL1	ENST00000887846.1		c.596G>T	p.Arg199Leu	missense	Exon 7 of 7	ENSP00000557905.1
	DERL1	ENST00000405944.7	TSL:2	c.563G>T	p.Arg188Leu	missense	Exon 8 of 8	ENSP00000384289.3	Q9BUN8-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455452 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723606

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 43870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.00 AC: 0 AN: 84526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108900

Other (OTH) AF: 0.00 AC: 0 AN: 60180

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.028
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.12
Sift	Uncertain	0.018	D
Sift4G	Benign	0.073	T
Polyphen		0.097	B
Vest4		0.58
MutPred		0.48		Loss of MoRF binding (P = 0.0152)
MVP		0.64
MPC		0.48
ClinPred		0.98	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.89
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: rs141975370; hg19: chr8-124027820;