Genetic Variant NM_032885.6:c.915C>T (chr19-10548983-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_032885.6(ATG4D):c.915C>T(p.Pro305Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,798 control chromosomes in the GnomAD database, including 16,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P305P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1462 hom., cov: 31)

Exomes 𝑓: 0.14 ( 14989 hom. )

Consequence

ATG4D
NM_032885.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.42

Publications

19 publications found

Variant links:

Genes affected

ATG4D (HGNC:20789): (autophagy related 4D 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 belongs to the autophagy-related protein 4 (Atg4) family of C54 endopeptidases. Members of this family encode proteins that play a role in the biogenesis of autophagosomes, which sequester the cytosol and organelles for degradation by lysosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ATG4D Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

ATG4D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 19-10548983-C-T is Benign according to our data. Variant chr19-10548983-C-T is described in ClinVar as Benign. ClinVar VariationId is 1290655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.42 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032885.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATG4D	NM_032885.6	MANE Select	c.915C>T	p.Pro305Pro	synonymous	Exon 6 of 10	NP_116274.3
ATG4D	NM_001281504.2		c.726C>T	p.Pro242Pro	synonymous	Exon 6 of 10	NP_001268433.1
ATG4D	NR_104024.2		n.1058C>T		non_coding_transcript_exon	Exon 6 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATG4D	ENST00000309469.9	TSL:1 MANE Select	c.915C>T	p.Pro305Pro	synonymous	Exon 6 of 10	ENSP00000311318.3
ATG4D	ENST00000588667.5	TSL:1	n.638C>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000467407.1
ATG4D	ENST00000588857.5	TSL:1	n.871C>T		non_coding_transcript_exon	Exon 6 of 10	ENSP00000468290.1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20318

AN:

151872

Hom.:

1463

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.343

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.160

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.142

GnomAD2 exomes

AF:

0.135

AC:

33932

AN:

251292

AF XY:

0.140

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.0953

Gnomad EAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.144

GnomAD4 exome

AF:

0.141

AC:

206075

AN:

1461808

Hom.:

14989

Cov.:

AF XY:

0.142

AC XY:

103428

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.114

AC:

3826

AN:

33478

American (AMR)

AF:

0.107

AC:

4773

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0981

AC:

2563

AN:

26134

East Asian (EAS)

AF:

0.105

AC:

4148

AN:

39684

South Asian (SAS)

AF:

0.183

AC:

15825

AN:

86252

European-Finnish (FIN)

AF:

0.138

AC:

7368

AN:

53418

Middle Eastern (MID)

AF:

0.180

AC:

1039

AN:

5768

European-Non Finnish (NFE)

AF:

0.142

AC:

157991

AN:

1111970

Other (OTH)

AF:

0.141

AC:

8542

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

10347

20694

31040

41387

51734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5748

11496

17244

22992

28740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.134

AC:

20333

AN:

151990

Hom.:

1462

Cov.:

AF XY:

0.137

AC XY:

10178

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.114

AC:

4727

AN:

41466

American (AMR)

AF:

0.122

AC:

1861

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

357

AN:

3468

East Asian (EAS)

AF:

0.119

AC:

614

AN:

5160

South Asian (SAS)

AF:

0.181

AC:

870

AN:

4806

European-Finnish (FIN)

AF:

0.160

AC:

1693

AN:

10580

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.140

AC:

9546

AN:

67958

Other (OTH)

AF:

0.142

AC:

299

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

876

1752

2629

3505

4381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.136

Hom.:

2741

Bravo

AF:

0.130

Asia WGS

AF:

0.157

AC:

546

AN:

3478

EpiCase

AF:

0.145

EpiControl

AF:

0.146

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.5

(source)

DANN

Benign

0.88

PhyloP100

-3.4

PromoterAI

0.0083

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over