Genetic Variant ATG4B:c.112+5C>T (chr2-241651116-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_013325.5(ATG4B):c.112+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00636 in 1,610,270 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 36 hom. )

Consequence

ATG4B
NM_013325.5 splice_region, intron

Scores

Splicing: ADA: 0.00008042

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.94

Variant links:

Genes affected

ATG4B (HGNC:20790): (autophagy related 4B cysteine peptidase) Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ATG4B links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 2-241651116-C-T is Benign according to our data. Variant chr2-241651116-C-T is described in ClinVar as [Benign]. Clinvar id is 787165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4B	NM_013325.5 link	c.112+5C>T		splice_region_variant, intron_variant	Intron 2 of 12	ENST00000404914.8	NP_037457.3	Q9Y4P1-1B3KVU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG4B	ENST00000404914.8 link	c.112+5C>T		splice_region_variant, intron_variant	Intron 2 of 12	1	NM_013325.5	ENSP00000384259.3		Q9Y4P1-1

Frequencies

GnomAD3 genomes

AF:

0.00503

AC:

765

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00778

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00530

AC:

1287

AN:

242676

Hom.:

AF XY:

0.00517

AC XY:

680

AN XY:

131460

show subpopulations

Gnomad AFR exome

AF:

0.000735

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.00333

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000371

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.00828

Gnomad OTH exome

AF:

0.00405

GnomAD4 exome

AF:

0.00650

AC:

9471

AN:

1457960

Hom.:

Cov.:

AF XY:

0.00627

AC XY:

4546

AN XY:

724960

show subpopulations

Gnomad4 AFR exome

AF:

0.000688

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.00299

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000409

Gnomad4 FIN exome

AF:

0.0123

Gnomad4 NFE exome

AF:

0.00750

Gnomad4 OTH exome

AF:

0.00466

GnomAD4 genome

AF:

0.00501

AC:

763

AN:

152310

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

366

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0121

Gnomad4 NFE

AF:

0.00778

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00615

Hom.:

Bravo

AF:

0.00411

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.16

DANN

Benign

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000080

dbscSNV1_RF

Benign

0.024

SpliceAI score (max)

0.010

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