8-123042073-T-C

Position:

chr8-123042073-T-C

Variant summary

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

The NM_024295.6(DERL1):c.50A>G(p.Tyr17Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

DERL1
NM_024295.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.38

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DERL1	NM_024295.6 linkuse as main transcript	c.50A>G	p.Tyr17Cys	missense_variant	1/8	ENST00000259512.9	NP_077271.1
DERL1	NM_001134671.3 linkuse as main transcript	c.50A>G	p.Tyr17Cys	missense_variant	1/8		NP_001128143.1
DERL1	NM_001330601.2 linkuse as main transcript	c.-139A>G		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.50A>G	p.Tyr17Cys	missense_variant	1/8	1	NM_024295.6	ENSP00000259512	P1	Q9BUN8-1
DERL1	ENST00000405944.7 linkuse as main transcript	c.50A>G	p.Tyr17Cys	missense_variant	1/8	2		ENSP00000384289		Q9BUN8-2
DERL1	ENST00000419562.6 linkuse as main transcript	c.50A>G	p.Tyr17Cys	missense_variant	1/4	2		ENSP00000389965
TBC1D31	ENST00000520368.5 linkuse as main transcript	c.-415T>C		5_prime_UTR_variant	1/3	4		ENSP00000428486

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250030

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135320

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461530

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

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

May 11, 2022

The c.50A>G (p.Y17C) 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 50, causing the tyrosine (Y) at amino acid position 17 to be replaced by a cysteine (C). 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

0.17

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.092

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.9

M;M;.

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.2

D;D;D

REVEL

Benign

0.28

Sift

Benign

0.049

D;D;D

Sift4G

Benign

0.10

T;T;T

Polyphen

0.069

B;B;D

Vest4

0.77

MutPred

0.69

Gain of catalytic residue at W18 (P = 0.056);Gain of catalytic residue at W18 (P = 0.056);Gain of catalytic residue at W18 (P = 0.056);

MVP

0.85

MPC

0.49

ClinPred

0.96

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.93

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