8-123042023-T-C

Variant names:

• chr8-123042023-T-C
• rs765222212
• NM_024295.6:c.100A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024295.6(DERL1):​c.100A>G​(p.Ile34Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I34N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DERL1 NM_024295.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

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]

TBC1D31 (HGNC:30888): (TBC1 domain family member 31) Located in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18676317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DERL1	NM_024295.6	c.100A>G	p.Ile34Val	missense_variant	Exon 1 of 8	ENST00000259512.9	NP_077271.1
DERL1	NM_001134671.3	c.100A>G	p.Ile34Val	missense_variant	Exon 1 of 8		NP_001128143.1
DERL1	NM_001330601.2	c.-89A>G		5_prime_UTR_variant	Exon 1 of 7		NP_001317530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DERL1	ENST00000259512.9	c.100A>G	p.Ile34Val	missense_variant	Exon 1 of 8	1	NM_024295.6	ENSP00000259512.3
DERL1	ENST00000405944.7	c.100A>G	p.Ile34Val	missense_variant	Exon 1 of 8	2		ENSP00000384289.3
DERL1	ENST00000419562.6	c.100A>G	p.Ile34Val	missense_variant	Exon 1 of 4	2		ENSP00000389965.2
TBC1D31	ENST00000520368	c.-465T>C		5_prime_UTR_variant	Exon 1 of 3	4		ENSP00000428486.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250004 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000547 AC: 8 AN: 1461586 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.100A>G (p.I34V) alteration is located in exon 1 (coding exon 1) of the DERL1 gene. This alteration results from a A to G substitution at nucleotide position 100, causing the isoleucine (I) at amino acid position 34 to be replaced by a valine (V). 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	Benign	0.082
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.66
DEOGEN2	Benign	0.036	T;.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.45	N;N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.076
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.56	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.074
MutPred		0.63		Loss of catalytic residue at P36 (P = 0.0306);Loss of catalytic residue at P36 (P = 0.0306);Loss of catalytic residue at P36 (P = 0.0306);
MVP		0.58
MPC		0.27
ClinPred		0.044	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.74

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

Other links and lift over

dbSNP: rs765222212; hg19: chr8-124054263;