chr8-123042022-A-T

Position:

• chr8-123042022-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024295.6(DERL1):​c.101T>A​(p.Ile34Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DERL1 NM_024295.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DERL1	NM_024295.6	c.101T>A	p.Ile34Asn	missense_variant	1/8	ENST00000259512.9	NP_077271.1
DERL1	NM_001134671.3	c.101T>A	p.Ile34Asn	missense_variant	1/8		NP_001128143.1
DERL1	NM_001330601.2	c.-88T>A		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	c.101T>A	p.Ile34Asn	missense_variant	1/8	1	NM_024295.6	ENSP00000259512	P1
DERL1	ENST00000405944.7	c.101T>A	p.Ile34Asn	missense_variant	1/8	2		ENSP00000384289
DERL1	ENST00000419562.6	c.101T>A	p.Ile34Asn	missense_variant	1/4	2		ENSP00000389965
TBC1D31	ENST00000520368.5	c.-466A>T		5_prime_UTR_variant	1/3	4		ENSP00000428486

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.101T>A (p.I34N) alteration is located in exon 1 (coding exon 1) of the DERL1 gene. This alteration results from a T to A substitution at nucleotide position 101, causing the isoleucine (I) at amino acid position 34 to be replaced by an asparagine (N). 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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Pathogenic	3.1	M;M;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.59	P;P;B
Vest4		0.79
MutPred		0.76		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		0.81
MPC		1.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.91
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-124054262;