Genetic Variant NM_024295.6:c.101T>A (chr8-123042022-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I34V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

DERL1
NM_024295.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.45

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

congenital anomaly of kidney and urinary tract
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

TBC1D31 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.882

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DERL1	NM_024295.6	MANE Select	c.101T>A	p.Ile34Asn	missense	Exon 1 of 8	NP_077271.1	Q9BUN8-1
DERL1	NM_001134671.3		c.101T>A	p.Ile34Asn	missense	Exon 1 of 8	NP_001128143.1	Q9BUN8-2
DERL1	NM_001330601.2		c.-88T>A		5_prime_UTR	Exon 1 of 7	NP_001317530.1	E5RGY0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DERL1	ENST00000259512.9	TSL:1 MANE Select	c.101T>A	p.Ile34Asn	missense	Exon 1 of 8	ENSP00000259512.3	Q9BUN8-1
TBC1D31	ENST00000520368.5	TSL:4	c.-466A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000428486.1	E5RI27
DERL1	ENST00000940123.1		c.101T>A	p.Ile34Asn	missense	Exon 1 of 8	ENSP00000610182.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.086

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.72

MutationAssessor

Pathogenic

3.1

PhyloP100

5.5

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.36

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

0.59

Vest4

0.79

MutPred

0.76

Loss of catalytic residue at P36 (P = 0.0306)

MVP

0.81

MPC

1.0

ClinPred

1.0

GERP RS

4.7

PromoterAI

0.0036

Neutral

(source)

Varity_R

0.91

gMVP

0.97

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over