Genetic Variant DLEC1:p.Gln1043Arg (chr3-38108514-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007335.4(DLEC1):c.3128A>G(p.Gln1043Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

DLEC1
NM_007335.4 missense, splice_region

Scores

Splicing: ADA: 0.01331

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.135

Variant links:

Genes affected

DLEC1 (HGNC:2899): (DLEC1 cilia and flagella associated protein) The cytogenetic location of this gene is 3p21.3, and it is located in a region that is commonly deleted in a variety of malignancies. Down-regulation of this gene has been observed in several human cancers including lung, esophageal, renal tumors, and head and neck squamous cell carcinoma. In some cases, reduced expression of this gene in tumor cells is a result of aberrant promoter methylation. Several alternatively spliced transcripts have been observed that contain disrupted coding regions and likely encode nonfunctional proteins.[provided by RefSeq, Mar 2016]

DLEC1 links:

ACAA1 (HGNC:82): (acetyl-CoA acyltransferase 1) This gene encodes an enzyme operative in the beta-oxidation system of the peroxisomes. Deficiency of this enzyme leads to pseudo-Zellweger syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACAA1 links:

LOC105377033 (HGNC:):

LOC105377033 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043254793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLEC1	NM_007335.4 link	c.3128A>G	p.Gln1043Arg	missense_variant, splice_region_variant	Exon 21 of 37	ENST00000308059.11	NP_031361.2	Q9Y238-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLEC1	ENST00000308059.11 link	c.3128A>G	p.Gln1043Arg	missense_variant, splice_region_variant	Exon 21 of 37	1	NM_007335.4	ENSP00000308597.6	Q9Y238-1
DLEC1	ENST00000346219.7 link	c.3128A>G	p.Gln1043Arg	missense_variant, splice_region_variant	Exon 21 of 36	1		ENSP00000315914.5	Q9Y238-3
ACAA1	ENST00000451419.1 link	n.300-4721T>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460960

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726814

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

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

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3128A>G (p.Q1043R) alteration is located in exon 21 (coding exon 21) of the DLEC1 gene. This alteration results from a A to G substitution at nucleotide position 3128, causing the glutamine (Q) at amino acid position 1043 to be replaced by an arginine (R). 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

0.080

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

1.5

DANN

Benign

0.84

DEOGEN2

Benign

0.010

.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.48

T;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.043

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.025

Sift

Benign

0.51

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0030

B;B

Vest4

0.12

MutPred

0.25

Loss of glycosylation at T1039 (P = 0.0692);Loss of glycosylation at T1039 (P = 0.0692);

MVP

0.39

MPC

0.12

ClinPred

0.049

GERP RS

0.81

Varity_R

0.081

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.013

dbscSNV1_RF

Benign

0.30

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over