Variant 8-123041989-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024295.6(DERL1):c.134C>T(p.Ala45Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DERL1
NM_024295.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.43

Variant links:

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]

DERL1 links:

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

TBC1D31 links:

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ACMG classification

Classification made for transcript

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=0.20185077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DERL1	NM_024295.6 linkuse as main transcript	c.134C>T	p.Ala45Val	missense_variant	1/8	ENST00000259512.9	NP_077271.1
DERL1	NM_001134671.3 linkuse as main transcript	c.134C>T	p.Ala45Val	missense_variant	1/8		NP_001128143.1
DERL1	NM_001330601.2 linkuse as main transcript	c.-55C>T		5_prime_UTR_variant	1/7		NP_001317530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DERL1	ENST00000259512.9 linkuse as main transcript	c.134C>T	p.Ala45Val	missense_variant	1/8	1	NM_024295.6	ENSP00000259512	P1	Q9BUN8-1
DERL1	ENST00000405944.7 linkuse as main transcript	c.134C>T	p.Ala45Val	missense_variant	1/8	2		ENSP00000384289		Q9BUN8-2
DERL1	ENST00000419562.6 linkuse as main transcript	c.134C>T	p.Ala45Val	missense_variant	1/4	2		ENSP00000389965
TBC1D31	ENST00000520368.5 linkuse as main transcript	c.-499G>A		5_prime_UTR_variant	1/3	4		ENSP00000428486

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248820

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000873

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:

0.00000205

AC:

AN:

1460252

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000673

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

The c.134C>T (p.A45V) alteration is located in exon 1 (coding exon 1) of the DERL1 gene. This alteration results from a C to T substitution at nucleotide position 134, causing the alanine (A) at amino acid position 45 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

0.20

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.042

T;.;T

Eigen

Benign

-0.065

Eigen_PC

Benign

0.042

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.0083

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;.

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.84

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.62

T;T;T

Sift4G

Benign

0.56

T;T;T

Polyphen

0.053

B;B;P

Vest4

0.46

MutPred

0.55

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);

MVP

0.70

MPC

0.37

ClinPred

0.90

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over